IMMUNODEFICIENCY NEXT-GENERATION SEQUENCING PANELS · 2019-07-31 · SEVERE COMBINED IMMUNODEFICIENCY (SCID) SUBPANEL 36 REFERENCES 38 DISCLAIMER 46. Mail: One Gustave L. Levy Place,

Mail: One Gustave L. Levy Place, Box 1497 Specimens: 1428 Madison Ave, Atran Bldg, Rm 2-25 New York, NY 10029

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CLIA #: 33D2097541 T: 800-298-6470 F: 212-241-0139 www.sema4genomics.com

IMMUNODEFICIENCY NEXT-GENERATION SEQUENCING PANELS

Mail: One Gustave L. Levy Place, Box 1497 Specimens: 1428 Madison Ave, Atran Bldg, Rm 2-25 New York, NY 10029 2




Table of Contents

GENETIC TESTING FOR IMMUNODEFICIENCY 4

GENETICS 4 INDICATIONS 4 TESTING METHODS, SENSITIVITY, AND LIMITATIONS 4 TURNAROUND TIME 7 SPECIMEN AND SHIPPING REQUIREMENTS 7 CUSTOMER SERVICES AND GENETIC COUNSELING 8

THE COMPREHENSIVE IMMUNODEFIENCY PANEL 9

PRIMARY IMMUNODEFIENCY (PID) SUBPANEL 22

INFLAMMATORY BOWEL DISEASE (IBD) SUBPANEL 32

SEVERE COMBINED IMMUNODEFICIENCY (SCID) SUBPANEL 36

REFERENCES 38

DISCLAIMER 46



Genetic Testing for IMMUNODEFICIENCY Inherited disorders of the immune system include over 300 known diseases in the world with prevalence rates of more than 1 in 1,000 in the US (Joshi, et al 2009). Genetic defects constitute the vast majority and are the main driver of immunological diseases with diagnosable causes (Zhernakova, et al 2009). Symptoms and severity range from mild increases in susceptibility to infection and gastrointestinal disorders to the inability to survive in non-sterile environments. Sema4 utilizes Agilent SureSelectQXT target enrichment library prep with Illumina NovaSeq NGS platform to detect clinically significant variants in immunodeficiency-related genes selected based on available evidence to date. The genes in this panel and subpanels were curated based on careful consideration of literature review, active physician input, and comparison against existing tests. The Comprehensive Panel includes 250 genes with the following subpanels: Primary Immunodeficiency (PID; 206), Inflammatory Bowel Disease (IBD; 59), and Severe Combined Immunodeficiency (SCID; 26). Our results aim to pinpoint the genetic basis of a patient’s immunological disease thereby aiding physicians when developing healthcare plans and allowing genetic counselors to advise the patient in family planning and carrier status relative risk for family members. Genetics The disorders included in this panel may be inherited in an autosomal dominant (AD), autosomal recessive (AR), X-linked (XL), or isolated cases (IC) manner. For genes displaying an AD mode of inheritance, an affected parent carrying the mutated gene has a 50% chance of passing the variant on to an offspring, regardless of gender. Some of these genes are not fully penetrant, meaning that an individual may have a mutated gene but not display any of the signs/symptoms of the disorder. Additionally, these disorders may have variable expressivity indicating that individuals carrying the same pathogenic variant may display differing features and/or differing severity. For diseases with AR inheritance, the risk for a couple who are both carriers to have a child affected with the disease is 25% for each pregnancy. The parents of an affected child are most often obligate carriers (heterozygotes) and each carry one mutant allele (unless a de novo mutation occurs). An X-linked inheritance means that the risk of a male offspring with the disorder will be 50% if the mother carries an XL mutation. Depending on the X-inactivation pattern of the gene, a mother and her daughters may rarely be affected. Although X-linked diseases are normally transmitted from mother to son, transmission of an X-linked mutation will occur from an affected father to each daughter, but will not occur from father to son. An IC mode of inheritance indicates no prior family history. Indications 1. Clinical status: to confirm a clinical diagnosis in an affected patient, in an individual with unknown status (no

screening/evaluation), or in unaffected relatives of an affected patient (all screening/evaluations(s) normal). The purpose of the test may be diagnostic, carrier testing, familial follow-up on a known family variant, or prenatal testing for known variant(s).

2. Treatment: to clarify the cause of an individual’s immunodeficiency and/or inflammatory bowel disease,

provide information on the likelihood of related health issues, and guide treatment. 3. Family risk: to establish risk to other family members and future generations.

For patients with a suspected syndrome or disorder, please consider single gene sequencing or associated subpanels prior to ordering the comprehensive panel.

Testing Methods, Sensitivity, and Limitations Next Generation Sequencing (NGS) (Analytical Detection Rate >95%) Agilent SureSelectTM QXT technology is used with a custom capture library to target the exonic regions and intron/exon splice junctions of the relevant genes, as well as a number of UTR, intronic or promoter regions that



contain previously reported mutations. Samples are pooled and sequenced on the Illumina NovaSeq platform in the Xp workflow, using 100 bp paired-end reads. The sequencing data are analyzed using a custom bioinformatics algorithm designed and validated in-house. In our validation, average coverage was greater than 200X per sample with >99.9% of regions covered at greater than 20X. The coding exons and splice junctions of the known protein-coding RefSeq genes are assessed for the average depth of coverage (minimum of 20X) and data quality threshold values. Most exons not meeting a minimum of >20X read depth across the exon are further analyzed by Sanger sequencing. Please note that several genomic regions present difficulties in mapping or obtaining read depth >20X. These regions include, but are not limited to, UTRs, promoters, and deep intronic areas. In addition, a mutation(s) in a gene not included on the panel could be present in this patient. The following regions (hg19 coordinates) have been excluded due to lack of amenability to NGS or Sanger sequencing, high GC content, high homology, lack of known clinically significant variants, or overlap with repetitive regions: C4A chr6:31959812-31960020, C4A chr6:31962010-31962172, C4A chr6:31968818-31968943, C4A chr6:31964594-31964849, C4A chr6:31961479-31961613, C4A chr6:31961681-31961774, C4A chr6:31962717-31962791, C4A chr6:31962870-31962982, C4A chr6:31963095-31963327, C4A chr6:31949873-31949960, C4A chr6:31950070-31950291, C4A chr6:31950483-31950707, C4A chr6:31950894-31950987, C4A chr6:31951043-31951154, C4A chr6:31951350-31951455, C4A chr6:31951603-31951722, C4A chr6:31951838-31951966, C4A chr6:31952041-31952196, C4A chr6:31958957-31959095, C4A chr6:31959172-31959374, C4A chr6:31959497-31959702, C4A chr6:31960151-31960332, C4A chr6:31960561-31960710, C4A chr6:31960855-31960952, C4A chr6:31961190-31961410, C4A chr6:31965470-31965552, C4A chr6:31966579-31966695, C4A chr6:31966770-31966979, C4A chr6:31967071-31967184, C4A chr6:31967252-31967349, C4A chr6:31969086-31969198, C4A chr6:31969261-31969382, C4A chr6:31969542-31969648, C4A chr6:31969888-31970043, C4A chr6:31970164-31970328, C4A chr6:31962263-31962495, C4A chr6:31963484-31963582, C4A chr6:31963720-31963899, C4A chr6:31963972-31964111, C4A chr6:31964909-31965099, C4B chr6:31992550-31992758, C4B chr6:32001555-32001680, C4B chr6:31997331-31997586, C4B chr6:31992235-31992440, C4B chr6:31996458-31996637, C4B chr6:31994217-31994351, C4B chr6:31994419-31994512, C4B chr6:31995455-31995529, C4B chr6:31995608-31995720, C4B chr6:31995833-31996065, C4B chr6:31982611-31982698, C4B chr6:31982808-31983029, C4B chr6:31983221-31983445, C4B chr6:31983632-31983725, C4B chr6:31983781-31983892, C4B chr6:31984088-31984193, C4B chr6:31984341-31984460, C4B chr6:31984576-31984704, C4B chr6:31984779-31984934, C4B chr6:31991695-31991833, C4B chr6:31991910-31992112, C4B chr6:31992889-31993070, C4B chr6:31993299-31993448, C4B chr6:31993593-31993690, C4B chr6:31993928-31994148, C4B chr6:31998207-31998289, C4B chr6:31999316-31999432, C4B chr6:31999507-31999716, C4B chr6:31999808-31999921, C4B chr6:31999989-32000086, C4B chr6:32001823-32001935, C4B chr6:32001998-32002119, C4B chr6:32002279-32002385, C4B chr6:32002625-32002780, C4B chr6:32002901-32003065, C4B chr6:31995001-31995233, C4B chr6:31994748-31994910, C4B chr6:31996222-31996320, C4B chr6:31996710-31996849, C4B chr6:31997646-31997836, CCDC40 chr17:78010450-78010501, CFHR1 chr1:196788963-196789043, CFHR1 chr1:196799618-196799823, CFHR3 chr1:196759163-196759368, CORO1A chr16:30200169-30200296, CSF2RA chrX:1422142-1422266, CYBB chrX:37656945-37657156, DCLRE1C chr10:14966805-14967016, DUOX2 chr15:45403297-45403486, IKBKG chrX:153792522-153792687, IKBKG chrX:153784368-153784602, IKBKG chrX:153786735-153786876, IKBKG chrX:153788610-153788785, IKBKG chrX:153791013-153791179, IKBKG chrX:153792162-153792246, IKBKG chrX:153791762-153791927, IKBKG chrX:153789891-153790010, IRAK4 chr12:44178044-44178050, NCF1 chr7:74203371-74203515, NCF1 chr7:74202316-74202443, NCF1 chr7:74199516-74199656, NCF1 chr7:74197270-74197415, NCF1 chr7:74191601-74191704, NCF1 chr7:74197856-74197986, NCF1 chr7:74193591-74193779, NCF1 chr7:74202891-74203059, NCF1 chr7:74193416-74193514, NCF1 chr7:74195114-74195192, NCF1 chr7:74188367-74188461, PMS2 chr7:6026378-6027262, PMS2 chr7:6017207-6017432, PMS2 chr7:6022443-6022633, PMS2 chr7:6013018-6013184, SLC37A4 chr11:118901156-118901367, STAT5B chr17:40370729-40370907, STAT5B chr17:40371318-40371492, STAT5B chr17:40371718-40371871, and TBX1 chr22:19748416-19748814. The exons contained within these regions will not be reflexed to Sanger sequencing if the mapping quality or coverage is poor due to high sequence homology. Any variants identified during testing in these regions are confirmed by a second method and reported. This test will detect variants within the exons and the intron-exon boundaries of the target regions. Variants outside these regions may not be detected, including, but not limited to, UTRs, promoters, and deep intronic areas, or regions that fall into the exceptions mentioned above. This technology may not detect all small



insertion/deletions and is not diagnostic for repeat expansions and structural genomic variation. In addition, a mutation(s) in a gene not included on the panel could be present in this patient. Copy Number Variant Analysis (Analytical Detection Rate >90%) Large duplications and deletions were called from the relative read depths on an exon-by-exon basis using a custom Exome Hidden Markov Model (XHMM) algorithm. This algorithm is designed to pick up deletions and duplications of two or more exons/probed regions in length. For deletions (³2 exons/probed regions), the analytical sensitivity and analytical specificity are >99%. For duplications (³2 exons/probed regions), the analytical sensitivity is >80% and analytical specificity is >99%. All reported pathogenic or likely pathogenic deletions and/or duplications were confirmed by a custom aCGH platform, quantitative PCR, and/or MLPA, depending on CNV size and gene content. Exon Array (Confirmation method) (Accuracy >99%) The customized oligonucleotide microarray (Oxford Gene Technology) is a highly-targeted exon-focused array capable of detecting medically relevant microdeletions and microduplications at a much higher resolution than traditional aCGH methods. Each array matrix has approximately one hundred and eighty thousand 60-mer oligonucleotide probes that cover the entire gene panel. This platform is designed based on human genome NCBI Build 37 (hg19) and the CGH probes are selected to target the exonic regions of 219 genes. This test does not include analysis of ACD, CLPB, COPA, CTPS1, DCLRE1B, DOCK2, EPG5, FCN1, IL17RC, IL18, IL21, INO80, IRF7, ISG15, JAGN1, JAK1, NFAT5, NFKB1, NLRC4, PGM3, POLE, PRKCD, RBCK1, RORC, SLC9A3, TNFAIP3, TNFSF12, TRIM22, TRNT1, TTC7A, and VPS45. For the majority of genes there are a minimum of 4 probes per exon. For very large exons, probes are distributed evenly along the exon with 1 probe every 125 bp. In the untargeted backbone regions, this array has one probe every 42kb. All genomic coordinates are reported using human genome NCBI Build 37 (hg19). Copy number aberrations are identified using the Aberration Detection Method-2 (ADM2) algorithm with a sensitivity threshold of 6.0 (Agilent Technologies). The log2 ratio threshold values to detect aberrations are < -0.25 for copy number losses and > 0.25 for copy number gains. Please note that any inconsistencies in the reported biological familial relationships could significantly change the interpretation of these results. For reported CNVs with uncertain clinical significance, continued surveillance of the medical literature for new information is recommended. The sensitivity of this assay is estimated to be greater than 99% for microdeletions and microduplications in the exonic regions of 219 medically-relevant genes. Variant interpretation and classification is performed based on the American College of Medical Genetics standards and guidelines for the interpretation of sequence variants (Richards et al, 2015). Frequency in control populations is evaluated based on the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org/), the Database of Genomic Variants (http://dgv.tcag.ca/dgv/app/home), and 1000 genomes (http://www.1000genomes.org/) databases. Any benign polymorphisms identified during this analysis will not be reported. Variant interpretations, based on current knowledge, may change over time as more information arises. The following aberrations will NOT be reported and parental studies will NOT be performed: • CNVs that are considered benign based on coverage in the Database of Genomic Variants (DGV;

<http://dgv.tcag.ca/>) and/or our internal laboratory CNV database • Gains or losses of <500 kb that do not include any known genes (<http://www.ncbi.nlm.nih.gov/refseq/>) • Gains or losses with no known clinical significance (based on gene content and/or coverage in the DGV) • Copy number variation of ACD, CLPB, COPA, CTPS1, DCLRE1B, DOCK2, EPG5, FCN1, IL17RC, IL18,

IL21, INO80, IRF7, ISG15, JAGN1, JAK1, NFAT5, NFKB1, NLRC4, PGM3, POLE, PRKCD, RBCK1, RORC, SLC9A3, TNFAIP3, TNFSF12, TRIM22, TRNT1, TTC7A, and VPS45.

• Copy number gains and losses associated with genetic susceptibility, quantitative trait loci, pharmacogenetic alleles, and cancer predisposition

• Copy number gains and losses that are < 1.0 Mb in size and that appear to be mosaic by aCGH due to atypical log2 ratios, unless the affected region is determined to be clinically significant based on gene content and/or coverage in the DGV



The aCGH technology cannot detect balanced rearrangements, such as reciprocal translocations, Robertsonian translocations, inversions and balanced insertions, or imbalances that are below the resolution of this array. This technology will also not detect point mutations or small insertion/deletions below this array’s resolution that cause frameshifts, imprinting defects or other epigenetic mutations, and may not detect low level mosaicism. The failure to detect an alteration at any locus does not exclude the diagnosis of any of the disorders represented on the microarray. The aCGH technology cannot detect balanced rearrangements, such as reciprocal translocations, Robertsonian translocations, inversions and balanced insertions, or imbalances that are below the resolution of this array. This technology will also not detect point mutations or small insertion/deletions below this array’s resolution that cause frameshifts, imprinting defects or other epigenetic mutations, and may not detect low level mosaicism. The failure to detect an alteration at any locus does not exclude the diagnosis of any of the disorders represented on the microarray. Quantitative PCR (Confirmation method) (Accuracy >99%) The relative quantification PCR is utilized on a Roche Universal Library Probe (UPL) system, which relates the PCR signal of the target region in one group to another. To test for genomic imbalances, both sample DNA and reference DNA is amplified with primer/probe sets that specific to the target region and a control region with known genomic copy number. Relative genomic copy numbers are calculated based on the standard ∆∆Ct formula. Sanger Sequencing (Confirmation method) (Accuracy >99%) Sanger sequencing, as indicated, is performed using BigDye Terminator chemistry with the ABI 3730 DNA analyzer with target specific amplicons. It also may be used to supplement specific guaranteed target regions that fail NGS sequencing due to poor quality or low depth of coverage (<20 reads) or as a confirmatory method for NGS positive results. False negative results may occur if rare variants interfere with amplification or annealing. Variant Interpretation and Reporting Variant interpretation and classification was performed based on the American College of Medical Genetics Standards and guidelines for the interpretation of sequence variants (PMID:25741868). Frequency in control populations were evaluated based on the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org/) , and Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/). Potentially pathogenic variants may be confirmed by Sanger sequencing if indicated. Familial samples are only tested for certain variants by Sanger sequencing if indicated. Variants classified as likely benign in the proband were not confirmed by Sanger sequencing. We cannot rule out the possibility that variants classified as uncertain clinical significance may contribute to disease. Any benign polymorphisms identified during this analysis were not reported. Variant interpretations, based on current knowledge, may change over time as more information arises. Turnaround Time Results are reported to the referring physician within 10-14 business days (for prenatal samples) and 3-4 weeks (for postnatal samples) from the receipt of the specimen. Please note only targeted analysis is performed for prenatal cases, where the familial gene and mutation(s) are known. Specimen and Shipping Requirements Postnatal blood samples: 2 yellow-top (ACD-A or ACD-B) or 2 lavender-top (EDTA) tubes, 5-10 mL of blood from the patient are required. One blood tube from both parents is requested. Newborn/child: 1 yellow-top (ACD-A or ACD-B) or 1 lavender-top (EDTA) tube, 2 mL of blood from the patient are required. Additionally, 1 yellow-top (ACD-A or ACD-B) or 1 lavender-top (EDTA) 5-10 mL tube of blood from both parents is requested.



Prenatal Specimens: 2 confluent T-25 flasks of cultured cells (originating from amniotic fluid or chorionic villi) or more than 4 mg of direct CVS tissue, or 15 mL of direct amniotic fluid (AF) as well as 1 lavender-top (EDTA) 5-10mL tube of blood from the pregnant patient and her partner are required. Note: parental blood samples are requested for confirmation studies necessary in some cases; maternal blood is also used for maternal cell contamination studies. Please note, prenatal analysis will only be performed for known parental variants. Extracted DNA samples: We request 20 µL DNA (50-250 ng/µL) or at minimum require 10 µL DNA (50-250 ng/µL). Causes for rejection include impurities in the test or reference DNA samples, including NaCl or KCl (>40 mM) and other salts, phenol, ethanol, heparin, EDTA (>1.5 mM), and Fe, contaminated DNA, and low concentration of DNA (<20 ng/µL). Saliva samples: We can accept saliva specimens upon request. Saliva samples should be collected in Oragene DNA (OG-500) kits by DNA Genotek. Please contact our laboratory to obtain saliva kits. Cheek swab: 1 cheek swab specimen collected from ORAGENE kit from the patient is required. 1 cheek swab specimen collected from ORAGENE kit from both parents is requested. Tubes of blood, cultured cells, direct CVS, and direct AF should be kept and shipped refrigerated or at room temperature (PLEASE DO NOT FREEZE). Please note that additional samples may be required for exon array studies if ordered. Customer Services and Genetic Counseling Include the following with each sample: • Completed and signed test requisition form and informed consent • Billing information or payment (include copy of insurance card) • Contact information for referring physician • Testing to be performed • Indication for testing, patient’s family history, ethnic background and prior relevant test results Send same day or overnight (check for morning delivery) to: Sema4 1428 Madison Avenue, Atran Bldg, Room 2-25 New York, NY 10029 Contact: [email protected] Tel: 212-241-7518 Fax: 212-241-0139



THE COMPREHENSIVE IMMUNODEFIENCY PANEL Inherited disorders of the immune system include over 300 known diseases in the world with prevalence rates of more than 1 in 1,000 in the US (Joshi, et al 2009). Genetic defects constitute the vast majority and are the main driver of immunological diseases with diagnosable causes (Zhernakova, et al 2009). Symptoms and severity range from mild increases in susceptibility to infection and gastrointestinal disorders to the inability to survive in non-sterile environments. The Comprehensive Panel includes 250 genes with the following subpanels: Primary Immunodeficiency (PID; 206), Inflammatory Bowel Disease (IBD; 59), and Severe Combined Immunodeficiency (SCID; 26). Further details about these subpanels are provided on subsequent pages. The Comprehensive Immunodeficiency Panel includes the following 250 genes.

Gene MIM Disease Category OMIM Phenotype Inheritance

ACD 609377 Comprehensive Immunodeficiency; Primary Immunodeficiency

616553: AR, AD ?Dyskeratosis congenita, AD 6 616553: AR, AD ?Dyskeratosis congenita, AR 7 AD, AR

ACP5 171640 Comprehensive Immunodeficiency; Primary Immunodeficiency

607944: AR Spondyloenchondrodysplasia with immune dysregulation AR

ADA 608958 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease; Severe Combined Immunodeficiency

102700: AR, Somatic mosaicism Adenosine deaminase deficiency, partial 102700: AR, Somatic mosaicism Severe combined immunodeficiency due to ADA deficiency

AR

ADA2 607575 Comprehensive Immunodeficiency; Primary Immunodeficiency

615688: AR Polyarteritis nodosa, childhood-onset 182410: AR ?Sneddon syndrome AR

ADAM17 603639 Comprehensive Immunodeficiency; Inflammatory Bowel Disease

614328: AR ?Inflammatory skin and bowel disease, neonatal, 1 AR

ADAR 146920 Comprehensive Immunodeficiency; Primary Immunodeficiency

615010: AR Aicardi-Goutieres syndrome 6 127400: AD Dyschromatosis symmetrica hereditaria AD, AR

AICDA 605257 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease

605258: AR Immunodeficiency with hyper-IgM, type 2 AR

AIRE 607358 Comprehensive Immunodeficiency; Primary Immunodeficiency

240300: AR, AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible AD, AR



Gene MIM Disease Category OMIM Phenotype Inheritance metaphyseal dysplasia

AK2 103020 Comprehensive Immunodeficiency; Primary Immunodeficiency; Severe Combined Immunodeficiency

267500: AR Reticular dysgenesis AR

AP3B1 603401 Comprehensive Immunodeficiency; Primary Immunodeficiency 608233: AR Hermansky-Pudlak syndrome 2 AR

B2M 109700 Comprehensive Immunodeficiency; Primary Immunodeficiency

105200: AD ?Amyloidosis, familial visceral 241600: AR Immunodeficiency 43 AD, AR

BTK 300300 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease

307200: XLR Agammaglobulinemia and isolated hormone deficiency 300755: XLR Agammaglobulinemia, XL 1

XLR, XL

C1QA 120550 Comprehensive Immunodeficiency; Primary Immunodeficiency 613652: AR C1q deficiency AR

C1QB 120570 Comprehensive Immunodeficiency; Primary Immunodeficiency 613652: AR C1q deficiency AR

C1QC 120575 Comprehensive Immunodeficiency; Primary Immunodeficiency 613652: AR C1q deficiency AR

C1S 120580 Comprehensive Immunodeficiency; Primary Immunodeficiency

613783: C1s deficiency 617174: AD Ehlers-Danlos syndrome, periodontal type, 2

AD

C2 613927 Comprehensive Immunodeficiency; Primary Immunodeficiency

217000: AR C2 deficiency 615489: {Macular degeneration, age-related, 14, reduced risk of}

AR

C3 120700 Comprehensive Immunodeficiency

613779: AR C3 deficiency 612925: AD {Hemolytic uremic syndrome, atypical, susceptibility to, 5} 611378: {Macular degeneration, age-related, 9}

AD, AR

C4A 120810 Comprehensive Immunodeficiency; Primary Immunodeficiency

614374: [Blood group, Rodgers] 614380: AR C4a deficiency AR

C4B 120820 Comprehensive Immunodeficiency 614379: C4B deficiency None


609536: C5 deficiency 615749: AD [Eculizumab, poor response to] AD

C6 217050 Comprehensive Immunodeficiency 612446: C6 deficiency Combined C6/C7 deficiency (3) None

C7 217070 Comprehensive Immunodeficiency 610102: C7 deficiency None C8A 120950 Comprehensive Immunodeficiency 613790: AR C8 deficiency, type I AR

C8B 120960 Comprehensive Immunodeficiency; Primary Immunodeficiency 613789: AR C8 deficiency, type II AR


613825: C9 deficiency 615591: {Macular degeneration, age-related, 15, susceptibility to}

None

CARD11 607210 Comprehensive Immunodeficiency; Primary Immunodeficiency

616452: AD B-cell expansion with NFKB and T-cell anergy 615206: AR Immunodeficiency 11A 617638: AD Immunodeficiency 11B with atopic dermatitis

AD, AR


173200: AD Pityriasis rubra pilaris 602723: AD Psoriasis 2 AD

CARD9 607212 Comprehensive Immunodeficiency; Primary Immunodeficiency 212050: AR Candidiasis, familial, 2, AR AR

CASP10 601762 Comprehensive Immunodeficiency; Primary Immunodeficiency

603909: AD Autoimmune lymphoproliferative syndrome, type II 613659: Gastric cancer, somatic 605027: Lymphoma, non-Hodgkin, somatic

AD


607271: AR ?Autoimmune lymphoproliferative syndrome, type IIB 114480: AD {Breast cancer, protection against} 114550: Hepatocellular carcinoma, somatic 211980: AR {Lung cancer, protection against}

AD, AR

CCDC39 613798 Comprehensive Immunodeficiency 613807: Ciliary dyskinesia, primary, 14 None CCDC40 613799 Comprehensive Immunodeficiency 613808: Ciliary dyskinesia, primary, 15 None

CD19 107265 Comprehensive Immunodeficiency; Primary Immunodeficiency 613493: AR Immunodeficiency, common variable, 3 AR




CD247 186780 Comprehensive Immunodeficiency; Primary Immunodeficiency; Severe Combined Immunodeficiency

610163: AR ?Immunodeficiency 25 AR

CD27 186711 Comprehensive Immunodeficiency; Primary Immunodeficiency 615122: AR Lymphoproliferative syndrome 2 AR

CD3D 186790 Comprehensive Immunodeficiency; Primary Immunodeficiency; Severe Combined Immunodeficiency

615617: AR Immunodeficiency 19 AR

CD3E 186830 Comprehensive Immunodeficiency; Primary Immunodeficiency; Severe Combined Immunodeficiency

615615: AR Immunodeficiency 18 615615: AR Immunodeficiency 18, SCID variant AR

CD3G 186740 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease

615607: AR Immunodeficiency 17, CD3 gamma deficient AR

CD40 109535 Comprehensive Immunodeficiency; Primary Immunodeficiency


CD40LG 300386 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease 308230: XLR Immunodeficiency, XL, with hyper-IgM XLR, XL


612922: AR, AD {Hemolytic uremic syndrome, atypical, susceptibility to, 2} AD, AR


612300: AR Hemolytic anemia, CD59-mediated, with or without immune-mediated polyneuropathy AR

CD79A 112205 Comprehensive Immunodeficiency; Primary Immunodeficiency 613501: AR Agammaglobulinemia 3 AR

CD79B 147245 Comprehensive Immunodeficiency; Primary Immunodeficiency 612692: AR Agammaglobulinemia 6 AR

CD81 186845 Comprehensive Immunodeficiency 613496: AR Immunodeficiency, common variable, 6 AR

CD8A 186910 Comprehensive Immunodeficiency; Primary Immunodeficiency 608957: AR CD8 deficiency, familial AR

CEBPE 600749 Comprehensive Immunodeficiency; Primary Immunodeficiency 245480: AR Specific granule deficiency AR

CFB 138470 Comprehensive Immunodeficiency

615561: ?Complement factor B deficiency 612924: AD {Hemolytic uremic syndrome, atypical, susceptibility to, 4} 615489: {Macular degeneration, age-related, 14, reduced risk of}

AD

CFD 134350 Comprehensive Immunodeficiency; Primary Immunodeficiency 613912: AR Complement factor D deficiency AR

CFH 134370 Comprehensive Immunodeficiency; Primary Immunodeficiency

126700: AD Basal laminar drusen 609814: AR, AD Complement factor H deficiency 235400: AR, AD {Hemolytic uremic syndrome, atypical, susceptibility to, 1} 610698: {Macular degeneration, age-related, 4}

AD, AR

CFHR1 134371 Comprehensive Immunodeficiency

235400: AR, AD {Hemolytic uremic syndrome, atypical, susceptibility to} 603075: AD {Macular degeneration, age-related, reduced risk of}

AD, AR

CFHR3 605336 Comprehensive Immunodeficiency

235400: AR, AD {Hemolytic uremic syndrome, atypical, susceptibility to} 603075: AD {Macular degeneration, age-related, reduced risk of}

AD, AR

CFI 217030 Comprehensive Immunodeficiency; Primary Immunodeficiency

610984: AR Complement factor I deficiency 612923: AD {Hemolytic uremic syndrome, atypical, susceptibility to, 3} 615439: AD {Macular degeneration, age-related, 13, susceptibility to}

AD, AR

CFP 300383 Comprehensive Immunodeficiency; Primary Immunodeficiency 312060: XLR Properdin deficiency, XL XLR, XL

CHD7 608892 Comprehensive Immunodeficiency; Primary Immunodeficiency

214800: AD CHARGE syndrome 612370: AD Hypogonadotropic hypogonadism 5 with or without anosmia

AD

CIITA 600005 Comprehensive Immunodeficiency; Primary Immunodeficiency

209920: AR Bare lymphocyte syndrome, type II, complementation group A 180300: {Rheumatoid arthritis, susceptibility to}

AR

CLPB 616254 Comprehensive Immunodeficiency; Primary 616271: AR 3-methylglutaconic aciduria, type VII, AR



Gene MIM Disease Category OMIM Phenotype Inheritance Immunodeficiency with cataracts, neurologic involvement and

neutropenia

COPA 601924 Comprehensive Immunodeficiency; Primary Immunodeficiency

616414: AD {Autoimmune interstitial lung, joint, and kidney disease} AD

CORO1A 605000 Comprehensive Immunodeficiency; Primary Immunodeficiency; Severe Combined Immunodeficiency


CR2 120650 Comprehensive Immunodeficiency; Primary Immunodeficiency

614699: AR Immunodeficiency, common variable, 7 610927: {Systemic lupus erythematosus, susceptibility to, 9}

AR

CSF2RA 306250 Comprehensive Immunodeficiency; Primary Immunodeficiency

300770: Surfactant metabolism dysfunction, pulmonary, 4 None

CSF3R 138971 Comprehensive Immunodeficiency; Primary Immunodeficiency 617014: AR Neutropenia, severe congenital, 7, AR AR

CTC1 613129 Comprehensive Immunodeficiency; Primary Immunodeficiency

612199: AR Cerebroretinal microangiopathy with calcifications and cysts AR

CTLA4 123890 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease

616100: AD Autoimmune lymphoproliferative syndrome, type V 609755: {Celiac disease, susceptibility to, 3} 601388: {Diabetes mellitus, insulin-dependent, 12} 140300: AD {Hashimoto thyroiditis} 152700: AD {Systemic lupus erythematosus, susceptibility to}

AD

CTPS1 123860 Comprehensive Immunodeficiency; Primary Immunodeficiency 615897: AR Immunodeficiency 24 AR

CTSC 602365 Comprehensive Immunodeficiency; Primary Immunodeficiency

245010: AR Haim-Munk syndrome 245000: AR Papillon-Lefevre syndrome 170650: AR Periodontitis 1, juvenile

AR

CXCR4 162643 Comprehensive Immunodeficiency; Primary Immunodeficiency

Myelokathexis, isolated (3) 193670: AD WHIM syndrome AD

CYBA 608508 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease

233690: AR Chronic granulomatous disease, autosomal, due to deficiency of CYBA AR

CYBB 300481 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease

306400: XLR Chronic granulomatous disease, XL 300645: XLR Immunodeficiency 34, mycobacteriosis, XL

XLR, XL

DCLRE1B 609683 Comprehensive Immunodeficiency; Primary Immunodeficiency None None

DCLRE1C 605988 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease; Severe Combined Immunodeficiency

603554: AR Omenn syndrome 602450: AR Severe combined immunodeficiency, Athabascan type

AR

DGKE 601440 Comprehensive Immunodeficiency; Primary Immunodeficiency

615008: AR {Hemolytic uremic syndrome, atypical, susceptibility to, 7} 615008: AR Nephrotic syndrome, type 7

AR

DKC1 300126 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease 305000: XLR Dyskeratosis congenita, XL XLR, XL

DNMT3B 602900 Comprehensive Immunodeficiency; Primary Immunodeficiency

242860: AR Immunodeficiency-centromeric instability-facial anomalies syndrome 1 AR

DOCK2 603122 Comprehensive Immunodeficiency; Primary Immunodeficiency 616433: AR Immunodeficiency 40 AR

DOCK8 611432 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease; Severe Combined Immunodeficiency

243700: AR Hyper-IgE recurrent infection syndrome, AR AR

DUOX2 606759 Comprehensive Immunodeficiency 607200: AR Thyroid dyshormonogenesis 6 AR

ELANE 130130 Comprehensive Immunodeficiency; Primary Immunodeficiency

162800: AD Neutropenia, cyclic 202700: AD Neutropenia, severe congenital 1, AD AD

EPCAM 185535 Comprehensive Immunodeficiency

613244: Colorectal cancer, hereditary nonpolyposis, type 8 613217: AR Diarrhea 5, with tufting enteropathy, congenital

AR

EPG5 615068 Comprehensive Immunodeficiency; Primary Immunodeficiency 242840: AR Vici syndrome AR

FADD 602457 Comprehensive Immunodeficiency; Primary Immunodeficiency

613759: AR Infections, recurrent, with encephalopathy, hepatic dysfunction, and AR



Gene MIM Disease Category OMIM Phenotype Inheritance cardiovascular malformations

FAS 134637 Comprehensive Immunodeficiency; Primary Immunodeficiency

601859: AD Autoimmune lymphoproliferative syndrome, type IA 601859: AD {Autoimmune lymphoproliferative syndrome} Squamous cell carcinoma, burn scar-related, somatic (3)

AD

FASLG 134638 Comprehensive Immunodeficiency; Primary Immunodeficiency

601859: AD Autoimmune lymphoproliferative syndrome, type IB 211980: AR {Lung cancer, susceptibility to}

AD, AR

FCN1 601252 Comprehensive Immunodeficiency; Primary Immunodeficiency None None

FERMT1 607900 Comprehensive Immunodeficiency 173650: AR Kindler syndrome AR

FERMT3 607901 Comprehensive Immunodeficiency; Primary Immunodeficiency 612840: AR Leukocyte adhesion deficiency, type III AR

FOXN1 600838 Comprehensive Immunodeficiency; Primary Immunodeficiency; Severe Combined Immunodeficiency

601705: AR T-cell immunodeficiency, congenital alopecia, and nail dystrophy AR

FOXP3 300292 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease

222100: AR {Diabetes mellitus, type I, susceptibility to} 304790: XLR Immunodysregulation, polyendocrinopathy, and enteropathy, XL

AR, XLR, XL

G6PC3 611045 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease

612541: AR Dursun syndrome 612541: AR Neutropenia, severe congenital 4, AR AR

G6PD 305900 Comprehensive Immunodeficiency; Primary Immunodeficiency

300908: XLD Hemolytic anemia, G6PD deficient (favism) 611162: {Resistance to malaria due to G6PD deficiency}

XLD

GATA2 137295 Comprehensive Immunodeficiency; Primary Immunodeficiency

614038: AD Emberger syndrome 614172: AD Immunodeficiency 21 601626: AD {Leukemia, acute myeloid, susceptibility to} 614286: {Myelodysplastic syndrome, susceptibility to}

AD


146255: AD Hypoparathyroidism, sensorineural deafness, and renal dysplasia AD

GFI1 600871 Comprehensive Immunodeficiency; Primary Immunodeficiency

607847: AD ?Neutropenia, nonimmune chronic idiopathic, of adults 613107: AD ?Neutropenia, severe congenital 2, AD

AD

GUCY2C 601330 Comprehensive Immunodeficiency 614616: AD Diarrhea 6 614665: AR Meconium ileus AD, AR

HAX1 605998 Comprehensive Immunodeficiency; Primary Immunodeficiency 610738: AR Neutropenia, severe congenital 3, AR AR

HPS1 604982 Comprehensive Immunodeficiency 203300: AR Hermansky-Pudlak syndrome 1 AR HPS4 606682 Comprehensive Immunodeficiency 614073: AR Hermansky-Pudlak syndrome 4 AR HPS6 607522 Comprehensive Immunodeficiency 614075: AR Hermansky-Pudlak syndrome 6 AR

ICOS 604558 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease 607594: AR Immunodeficiency, common variable, 1 AR

IFIH1 606951 Comprehensive Immunodeficiency; Primary Immunodeficiency

615846: AD Aicardi-Goutieres syndrome 7 182250: AD Singleton-Merten syndrome 1 AD

IFNGR1 107470 Comprehensive Immunodeficiency; Primary Immunodeficiency

600263: {H. pylori infection, susceptibility to} 610424: {Hepatitis B virus infection, susceptibility to} 209950: AR Immunodeficiency 27A, mycobacteriosis, AR 615978: AD Immunodeficiency 27B, mycobacteriosis, AD 607948: {Tuberculosis infection, protection against} 607948: {Tuberculosis, susceptibility to}

AD, AR

IFNGR2 147569 Comprehensive Immunodeficiency; Primary Immunodeficiency 614889: AR Immunodeficiency 28, mycobacteriosis AR

IGHM 147020 Comprehensive Immunodeficiency; Primary Immunodeficiency 601495: AR Agammaglobulinemia 1 AR

IGLL1 146770 Comprehensive Immunodeficiency; Primary 613500: AR Agammaglobulinemia 2 AR



Gene MIM Disease Category OMIM Phenotype Inheritance Immunodeficiency

IKBKB 603258 Comprehensive Immunodeficiency; Primary Immunodeficiency 615592: AR Immunodeficiency 15 AR

IKBKG 300248 Comprehensive Immunodeficiency; Primary Immunodeficiency

300291: Ectodermal dysplasia, hypohidrotic, with immune deficiency 300301: Ectodermal, dysplasia, anhidrotic, lymphedema and immunodeficiency 300636: XLR Immunodeficiency 33 300584: Immunodeficiency, isolated 308300: XLD Incontinentia pigmenti 300640: Invasive pneumococcal disease, recurrent isolated, 2

XLD, XLR

IL10 124092 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease

614395: {Graft-versus-host disease, protection against} 609423: {HIV-1, susceptibility to} 180300: {Rheumatoid arthritis, progression of}

None

IL10RA 146933 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease

613148: AR Inflammatory bowel disease 28, early onset, AR AR

IL10RB 123889 Comprehensive Immunodeficiency; Inflammatory Bowel Disease

610424: {Hepatitis B virus, susceptibility to} 612567: AR Inflammatory bowel disease 25, early onset, AR

AR

IL12B 161561 Comprehensive Immunodeficiency 614890: AR Immunodeficiency 29, mycobacteriosis AR

IL12RB1 601604 Comprehensive Immunodeficiency; Primary Immunodeficiency 614891: AR Immunodeficiency 30 AR

IL17F 606496 Comprehensive Immunodeficiency 613956: ?Candidiasis, familial, 6, AD AD

IL17RA 605461 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease 613953: AR Immunodeficiency 51 AR

IL17RC 610925 Comprehensive Immunodeficiency 616445: AR Candidiasis, familial, 9 AR IL18 600953 Comprehensive Immunodeficiency None None

IL18RAP 604509 Comprehensive Immunodeficiency None None

IL1RN 147679 Comprehensive Immunodeficiency

137215: AD {Gastric cancer risk after H. pylori infection} 612852: AR Interleukin 1 receptor antagonist deficiency 612628: {Microvascular complications of diabetes 4}

AD, AR

IL21 605384 Comprehensive Immunodeficiency; Inflammatory Bowel Disease

615767: AR ?Immunodeficiency, common variable, 11 AR

IL21R 605383 Comprehensive Immunodeficiency 147050: AD [IgE, elevated level of] 615207: AR Immunodeficiency 56 AD, AR

IL23R 607562 Comprehensive Immunodeficiency; Inflammatory Bowel Disease

612261: {Inflammatory bowel disease 17, protection against} 605606: {Psoriasis, protection against}

None


601942: {Diabetes, mellitus, insulin-dependent, susceptibility to, 10} 606367: AR Immunodeficiency 41 with lymphoproliferation and autoimmunity

AR

IL2RG 308380 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease; Severe Combined Immunodeficiency

312863: XLR Combined immunodeficiency, XL, moderate 300400: XLR Severe combined immunodeficiency, XL

XLR, XL

IL36RN 605507 Comprehensive Immunodeficiency; Primary Immunodeficiency 614204: AR Psoriasis 14, pustular AR

IL7R 146661 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease; Severe Combined Immunodeficiency

608971: AR Severe combined immunodeficiency, T-cell negative, B-cell/natural killer cell-positive type AR

INO80 610169 Comprehensive Immunodeficiency; Primary Immunodeficiency None None

IRAK4 606883 Comprehensive Immunodeficiency; Primary Immunodeficiency

607676: IRAK4 deficiency 610799: Invasive pneumococcal disease, recurrent isolated, 1

None

IRF7 605047 Comprehensive Immunodeficiency; Primary Immunodeficiency 616345: AR ?Immunodeficiency 39 AR




IRF8 601565 Comprehensive Immunodeficiency; Primary Immunodeficiency

614893: AD Immunodeficiency 32A, mycobacteriosis, AD 226990: AR Immunodeficiency 32B, monocyte and dendritic cell deficiency, AR

AD, AR

IRGM 608212 Comprehensive Immunodeficiency

612278: {Inflammatory bowel disease (Crohn disease) 19} 607948: {Mycobacterium tuberculosis, protection against}

None

ISG15 147571 Comprehensive Immunodeficiency; Primary Immunodeficiency 616126: AR Immunodeficiency 38 AR

ITGAM 120980 Comprehensive Immunodeficiency; Primary Immunodeficiency

609939: {Systemic lupus erythematous, association with susceptibility to, 6} None

ITGB2 600065 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease 116920: AR Leukocyte adhesion deficiency AR

ITK 186973 Comprehensive Immunodeficiency; Primary Immunodeficiency 613011: AR Lymphoproliferative syndrome 1 AR

JAGN1 616012 Comprehensive Immunodeficiency; Primary Immunodeficiency 616022: AR Neutropenia, severe congenital, 6, AR AR

JAK1 147795 Comprehensive Immunodeficiency; Primary Immunodeficiency None None

JAK3 600173 Comprehensive Immunodeficiency; Primary Immunodeficiency; Severe Combined Immunodeficiency

600802: AR SCID, AR, T-negative/B-positive type AR

LAMTOR2 610389 Comprehensive Immunodeficiency; Primary Immunodeficiency

610798: AR Immunodeficiency due to defect in MAPBP-interacting protein AR

LCK 153390 Comprehensive Immunodeficiency; Primary Immunodeficiency 615758: AR ?Immunodeficiency 22 AR

LIG1 126391 Comprehensive Immunodeficiency None None

LIG4 601837 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease; Severe Combined Immunodeficiency

606593: AR LIG4 syndrome 254500: SM {Multiple myeloma, resistance to} AR, SM

LPIN2 605519 Comprehensive Immunodeficiency; Primary Immunodeficiency 609628: Majeed syndrome None

LRBA 606453 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease

614700: AR Immunodeficiency, common variable, 8, with autoimmunity AR

LRRC8A 608360 Comprehensive Immunodeficiency 613506: AD ?Agammaglobulinemia 5 AD

LYST 606897 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease 214500: AR Chediak-Higashi syndrome AR

MAGT1 300715 Comprehensive Immunodeficiency; Primary Immunodeficiency

300853: Immunodeficiency, XL, with magnesium defect, Epstein-Barr virus infection and neoplasia XL

MALT1 604860 Comprehensive Immunodeficiency; Primary Immunodeficiency 615468: AR Immunodeficiency 12 AR

MAP3K14 604655 Comprehensive Immunodeficiency; Primary Immunodeficiency None None

MASP2 605102 Comprehensive Immunodeficiency; Primary Immunodeficiency 613791: AR MASP2 deficiency AR

MEFV 608107 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease

134610: AD Familial Mediterranean fever, AD 249100: AR Familial Mediterranean fever, AR AD, AR

MRE11 600814 Comprehensive Immunodeficiency 604391: AR Ataxia-telangiectasia-like disorder 1 AR

MVK 251170 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease

260920: AR Hyper-IgD syndrome 610377: AR Mevalonic aciduria 175900: AD Porokeratosis 3, multiple types

AD, AR

MYD88 602170 Comprehensive Immunodeficiency; Primary Immunodeficiency

153600: Macroglobulinemia, Waldenstrom, somatic 612260: Pyogenic bacterial infections, recurrent, due to MYD88 deficiency

None

MYO5B 606540 Comprehensive Immunodeficiency 251850: AR Microvillus inclusion disease AR

NBN 602667 Comprehensive Immunodeficiency; Primary Immunodeficiency

609135: Aplastic anemia 613065: Leukemia, acute lymphoblastic 251260: AR Nijmegen breakage syndrome

AR

NCF1 608512 Comprehensive Immunodeficiency 233700: AR Chronic granulomatous disease due to deficiency of NCF-1 AR

NCF2 608515 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease

233710: AR Chronic granulomatous disease due to deficiency of NCF-2 AR





613960: AR ?Granulomatous disease, chronic, AR, cytochrome b-positive, type III AR

NFAT5 604708 Comprehensive Immunodeficiency; Primary Immunodeficiency None None

NFKB1 164011 Comprehensive Immunodeficiency 616576: AD Immunodeficiency, common variable, 12 AD

NFKB2 164012 Comprehensive Immunodeficiency; Primary Immunodeficiency

615577: AD Immunodeficiency, common variable, 10 AD

NFKBIA 164008 Comprehensive Immunodeficiency; Primary Immunodeficiency

612132: AD Ectodermal dysplasia, anhidrotic, with T-cell immunodeficiency AD

NHEJ1 611290 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease; Severe Combined Immunodeficiency

611291: Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation

None

NHP2 606470 Comprehensive Immunodeficiency; Primary Immunodeficiency 613987: AR Dyskeratosis congenita, AR 2 AR

NLRC4 606831 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease

616050: AD Autoinflammation with infantile enterocolitis 616115: AD ?Familial cold autoinflammatory syndrome 4

AD

NLRP12 609648 Comprehensive Immunodeficiency; Primary Immunodeficiency

611762: AD Familial cold autoinflammatory syndrome 2 AD


607115: AD CINCA syndrome 617772: AD Deafness, AD 34, with or without inflammation 120100: AD Familial cold inflammatory syndrome 1 148200: AD Keratoendothelitis fugax hereditaria 191900: AD Muckle-Wells syndrome

AD

NOD2 605956 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease

186580: AD Blau syndrome 266600: MF {Inflammatory bowel disease 1, Crohn disease} 607507: {Psoriatic arthritis, susceptibility to} 617321: MF {Yao syndrome}

AD, MF

NOP10 606471 Comprehensive Immunodeficiency; Primary Immunodeficiency 224230: AR Dyskeratosis congenita, AR 1 AR

NRAS 164790 Comprehensive Immunodeficiency; Primary Immunodeficiency

114500: Colorectal cancer, somatic 162900: Epidermal nevus, somatic 137550: Melanocytic nevus syndrome, congenital, somatic 249400: Neurocutaneous melanosis, somatic 613224: AD Noonan syndrome 6 614470: ?RAS-associated autoimmune lymphoproliferative syndrome type IV, somatic 163200: Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic 188470: Thyroid carcinoma, follicular, somatic

AD

ORAI1 610277 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease; Severe Combined Immunodeficiency

612782: AR Immunodeficiency 9 615883: AD Myopathy, tubular aggregate, 2 AD, AR

PGM3 172100 Comprehensive Immunodeficiency; Primary Immunodeficiency 615816: AR Immunodeficiency 23 AR

PIK3CD 602839 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease 615513: AD Immunodeficiency 14 AD

PIK3R1 171833 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease

615214: AR ?Agammaglobulinemia 7, AR 616005: AD Immunodeficiency 36 269880: AD SHORT syndrome

AD, AR

PLCG2 600220 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease

614878: AD Autoinflammation, antibody deficiency, and immune dysregulation syndrome 614468: AD Familial cold autoinflammatory syndrome 3

AD

PMS2 600259 Comprehensive Immunodeficiency 614337: Colorectal cancer, hereditary nonpolyposis, type 4 276300: AR Mismatch repair cancer syndrome

AR

PNP 164050 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease;

613179: AR Immunodeficiency due to purine nucleoside phosphorylase deficiency AR



Gene MIM Disease Category OMIM Phenotype Inheritance Severe Combined Immunodeficiency

POLE 174762 Comprehensive Immunodeficiency; Primary Immunodeficiency

615083: AD {Colorectal cancer, susceptibility to, 12} 615139: AR FILS syndrome AD, AR

PRF1 170280 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease

609135: Aplastic anemia 603553: AR Hemophagocytic lymphohistiocytosis, familial, 2 605027: Lymphoma, non-Hodgkin

AR

PRKCD 176977 Comprehensive Immunodeficiency; Primary Immunodeficiency

615559: AR Autoimmune lymphoproliferative syndrome, type III AR

PRKDC 600899 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease; Severe Combined Immunodeficiency

615966: AR Immunodeficiency 26, with or without neurologic abnormalities AR

PTEN 601728 Comprehensive Immunodeficiency

153480: Bannayan-Riley-Ruvalcaba syndrome 158350: AD Cowden syndrome 1 613028: {Glioma susceptibility 2} 158350: AD Lhermitte-Duclos syndrome 605309: AD Macrocephaly/autism syndrome 607174: AD {Meningioma} PTEN hamartoma tumor syndrome (3) 176807: {Prostate cancer, somatic} 276950: AR VATER association with macrocephaly and ventriculomegaly

AD, AR

PTPRC 151460 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease; Severe Combined Immunodeficiency

609532: {Hepatitis C virus, susceptibility to} 608971: AR Severe combined immunodeficiency, T cell-negative, B-cell/natural killer-cell positive

AR

RAB27A 603868 Comprehensive Immunodeficiency; Primary Immunodeficiency 607624: AR Griscelli syndrome, type 2 AR

RAC2 602049 Comprehensive Immunodeficiency; Primary Immunodeficiency; Severe Combined Immunodeficiency

608203: Neutrophil immunodeficiency syndrome None

RAG1 179615 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease; Severe Combined Immunodeficiency

609889: Alpha/beta T-cell lymphopenia with gamma/delta T-cell expansion, severe cytomegalovirus infection, and autoimmunity 233650: AR Combined cellular and humoral immune defects with granulomas 603554: AR Omenn syndrome 601457: AR Severe combined immunodeficiency, B cell-negative

AR


233650: AR Combined cellular and humoral immune defects with granulomas 603554: AR Omenn syndrome 601457: AR Severe combined immunodeficiency, B cell-negative

AR

RBCK1 610924 Comprehensive Immunodeficiency; Primary Immunodeficiency

615895: AR Polyglucosan body myopathy 1 with or without immunodeficiency AR

RET 164761 Comprehensive Immunodeficiency

209880: AD Central hypoventilation syndrome, congenital 142623: AD {Hirschsprung disease, protection against} 142623: AD {Hirschsprung disease, susceptibility to, 1} 155240: AD Medullary thyroid carcinoma 171400: AD Multiple endocrine neoplasia IIA 162300: AD Multiple endocrine neoplasia IIB 171300: AD Pheochromocytoma

AD

RFX5 601863 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease

209920: AR Bare lymphocyte syndrome, type II, complementation group C 209920: AR Bare lymphocyte syndrome, type II, complementation group E

AR

RFXANK 603200 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease

209920: AR MHC class II deficiency, complementation group B AR

RFXAP 601861 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease

209920: AR Bare lymphocyte syndrome, type II, complementation group D AR

RHOH 602037 Comprehensive Immunodeficiency; Primary None None




RMRP 157660 Comprehensive Immunodeficiency; Primary Immunodeficiency; Severe Combined Immunodeficiency

607095: AR Anauxetic dysplasia 1 250250: AR Cartilage-hair hypoplasia 250460: AR Metaphyseal dysplasia without hypotrichosis

AR

RNASEH2A 606034 Comprehensive Immunodeficiency; Primary Immunodeficiency 610333: AR Aicardi-Goutieres syndrome 4 AR

RNASEH2B 610326 Comprehensive Immunodeficiency; Primary Immunodeficiency 610181: AR Aicardi-Goutieres syndrome 2 AR

RNASEH2C 610330 Comprehensive Immunodeficiency; Primary Immunodeficiency 610329: AR Aicardi-Goutieres syndrome 3 AR

RORC 602943 Comprehensive Immunodeficiency; Primary Immunodeficiency 616622: AR Immunodeficiency 42 AR

RTEL1 608833 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease

615190: AR, AD Dyskeratosis congenita, AD 4 615190: AR, AD Dyskeratosis congenita, AR 5 616373: AD Pulmonary fibrosis and/or bone marrow failure, telomere-related, 3

AD, AR

SAMHD1 606754 Comprehensive Immunodeficiency; Primary Immunodeficiency

612952: AR Aicardi-Goutieres syndrome 5 614415: AD ?Chilblain lupus 2 AD, AR

SBDS 607444 Comprehensive Immunodeficiency 609135: {Aplastic anemia, susceptibility to} 260400: AR Shwachman-Diamond syndrome AR

SERPING1 606860 Comprehensive Immunodeficiency

106100: AR, AD Angioedema, hereditary, types I and II 120790: AD Complement component 4, partial deficiency of

AD, AR

SH2D1A 300490 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease 308240: XLR Lymphoproliferative syndrome, XL, 1 XLR, XL

SKIV2L 600478 Comprehensive Immunodeficiency; Primary Immunodeficiency 614602: AR Trichohepatoenteric syndrome 2 AR

SLC35C1 605881 Comprehensive Immunodeficiency; Primary Immunodeficiency

266265: AR Congenital disorder of glycosylation, type IIc AR

SLC37A4 602671 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease

232220: AR Glycogen storage disease Ib 232240: AR Glycogen storage disease Ic AR

SLC9A3 182307 Comprehensive Immunodeficiency 616868: AR Diarrhea 8, secretory sodium, congenital AR

SMARCAL1 606622 Comprehensive Immunodeficiency; Primary Immunodeficiency 242900: AR Schimke immunoosseous dysplasia AR

SP110 604457 Comprehensive Immunodeficiency; Primary Immunodeficiency

235550: AR Hepatic venoocclusive disease with immunodeficiency 607948: {Mycobacterium tuberculosis, susceptibility to}

AR

SPINK5 605010 Comprehensive Immunodeficiency; Primary Immunodeficiency 256500: AR Netherton syndrome AR

STAT1 600555 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease

614892: AD Immunodeficiency 31A, mycobacteriosis, AD 613796: AR Immunodeficiency 31B, mycobacterial and viral infections, AR 614162: AD Immunodeficiency 31C, AD

AD, AR


615952: AD Autoimmune disease, multisystem, infantile-onset, 1 147060: AD Hyper-IgE recurrent infection syndrome

AD

STAT5B 604260 Comprehensive Immunodeficiency; Primary Immunodeficiency; Severe Combined Immunodeficiency

245590: Growth hormone insensitivity with immunodeficiency 102578: Leukemia, acute promyelocytic, somatic

None

STIM1 605921 Comprehensive Immunodeficiency; Primary Immunodeficiency; Severe Combined Immunodeficiency

612783: AR Immunodeficiency 10 160565: AD Myopathy, tubular aggregate, 1 185070: AD Stormorken syndrome

AD, AR

STK4 604965 Comprehensive Immunodeficiency; Primary Immunodeficiency

614868: T-cell immunodeficiency, recurrent infections, autoimmunity, and cardiac malformations

None

STX11 605014 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease

603552: AR Hemophagocytic lymphohistiocytosis, familial, 4 AR

STXBP2 601717 Comprehensive Immunodeficiency; Primary 613101: Hemophagocytic lymphohistiocytosis, None



Gene MIM Disease Category OMIM Phenotype Inheritance Immunodeficiency; Inflammatory Bowel Disease familial, 5

TAP1 170260 Comprehensive Immunodeficiency; Primary Immunodeficiency 604571: AR Bare lymphocyte syndrome, type I AR

TAP2 170261 Comprehensive Immunodeficiency; Primary Immunodeficiency

604571: AR Bare lymphocyte syndrome, type I, due to TAP2 deficiency AR

TAPBP 601962 Comprehensive Immunodeficiency; Primary Immunodeficiency 604571: AR Bare lymphocyte syndrome, type I AR

TAZ 300394 Comprehensive Immunodeficiency; Primary Immunodeficiency 302060: XLR Barth syndrome XLR

TBX1 602054 Comprehensive Immunodeficiency; Primary Immunodeficiency; Severe Combined Immunodeficiency

217095: Conotruncal anomaly face syndrome 188400: AD DiGeorge syndrome 187500: AD Tetralogy of Fallot 192430: AD Velocardiofacial syndrome

AD

TCN2 613441 Comprehensive Immunodeficiency; Primary Immunodeficiency 275350: AR Transcobalamin II deficiency AR

TERC 602322 Comprehensive Immunodeficiency; Primary Immunodeficiency

614743: AD {Aplastic anemia} 127550: AD Dyskeratosis congenita, AD 1 614743: AD {Pulmonary fibrosis, idiopathic, susceptibility to}

AD

TERT 187270 Comprehensive Immunodeficiency; Primary Immunodeficiency

613989: AR, AD {Dyskeratosis congenita, AD 2} 613989: AR, AD {Dyskeratosis congenita, AR 4} 601626: AD {Leukemia, acute myeloid} 615134: {Melanoma, cutaneous malignant, 9} 614742: AD {Pulmonary fibrosis and/or bone marrow failure, telomere-related, 1}

AD, AR

TINF2 604319 Comprehensive Immunodeficiency; Primary Immunodeficiency

613990: AD Dyskeratosis congenita, AD 3 268130: AD Revesz syndrome AD

TLR3 603029 Comprehensive Immunodeficiency; Primary Immunodeficiency

613002: AR, AD {Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 2} 609423: {HIV1 infection, resistance to}

AD, AR

TMEM173 612374 Comprehensive Immunodeficiency; Primary Immunodeficiency

615934: AD STING-associated vasculopathy, infantile-onset AD

TNFAIP3 191163 Comprehensive Immunodeficiency; Primary Immunodeficiency

616744: AD Autoinflammatory syndrome, familial, Behcet-like AD

TNFRSF13B 604907 Comprehensive Immunodeficiency; Primary Immunodeficiency

240500: AR, AD Immunodeficiency, common variable, 2 609529: Immunoglobulin A deficiency 2

AD, AR

TNFRSF13C 606269 Comprehensive Immunodeficiency; Primary Immunodeficiency 613494: AR Immunodeficiency, common variable, 4 AR

TNFRSF1A 191190 Comprehensive Immunodeficiency; Primary Immunodeficiency

614810: {Multiple sclerosis, susceptibility to, 5} 142680: AD Periodic fever, familial AD

TNFSF12 602695 Comprehensive Immunodeficiency; Primary Immunodeficiency None None

TREX1 606609 Comprehensive Immunodeficiency; Primary Immunodeficiency

225750: AR, AD Aicardi-Goutieres syndrome 1, dominant and recessive 610448: AD Chilblain lupus 152700: AD {Systemic lupus erythematosus, susceptibility to} 192315: AD Vasculopathy, retinal, with cerebral leukodystrophy

AD, AR

TRIM22 606559 Comprehensive Immunodeficiency None None

TRNT1 612907 Comprehensive Immunodeficiency; Primary Immunodeficiency

616959: AR Retinitis pigmentosa and erythrocytic microcytosis 616084: AR Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay

AR

TTC37 614589 Comprehensive Immunodeficiency 222470: AR Trichohepatoenteric syndrome 1 AR

TTC7A 609332 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease

243150: AR Gastrointestinal defects and immunodeficiency syndrome AR

TYK2 176941 Comprehensive Immunodeficiency; Primary Immunodeficiency 611521: AR Immunodeficiency 35 AR

UNC13D 608897 Comprehensive Immunodeficiency; Primary Immunodeficiency

608898: Hemophagocytic lymphohistiocytosis, familial, 3 None




UNG 191525 Comprehensive Immunodeficiency; Primary Immunodeficiency

608106: AR Immunodeficiency with hyper IgM, type 5 AR

USB1 613276 Comprehensive Immunodeficiency; Primary Immunodeficiency 604173: AR Poikiloderma with neutropenia AR

VPS13B 607817 Comprehensive Immunodeficiency; Primary Immunodeficiency 216550: AR Cohen syndrome AR

VPS45 610035 Comprehensive Immunodeficiency; Primary Immunodeficiency 615285: AR Neutropenia, severe congenital, 5, AR AR

WAS 300392 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease

300299: XLR Neutropenia, severe congenital, XL 313900: XLR Thrombocytopenia, XL 313900: XLR Thrombocytopenia, XL, intermittent 301000: XLR Wiskott-Aldrich syndrome

XLR, XL

WIPF1 602357 Comprehensive Immunodeficiency; Primary Immunodeficiency 614493: ?Wiskott-Aldrich syndrome 2 None

WRAP53 612661 Comprehensive Immunodeficiency; Primary Immunodeficiency 613988: AR Dyskeratosis congenita, AR 3 AR

XIAP 300079 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease 300635: XLR Lymphoproliferative syndrome, XL, 2 XLR, XL

ZAP70 176947 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease; Severe Combined Immunodeficiency

617006: AR Autoimmune disease, multisystem, infantile-onset, 2 269840: AR Immunodeficiency 48

AR

ZBTB24 614064 Comprehensive Immunodeficiency; Primary Immunodeficiency


1. Abbreviations: Autosomal Dominant (AD); Autosomal Recession (AR); Isolated Cases (IC); Multifactorial (MF); Somatic Mutations (SM;

Note: somatic mutations are not reported); XL (X-linked); XLD (X-linked Dominant); and XLR (X-linked Recessive). 2. C4A: The following C4A hg19 coordinates have been excluded from this assay: chr6:31959812-31960020, chr6:31962010-31962172,

chr6:31968818-31968943, chr6:31964594-31964849, chr6:31961479-31961613, chr6:31961681-31961774, chr6:31962717-31962791, chr6:31962870-31962982, chr6:31963095-31963327, chr6:31949873-31949960, chr6:31950070-31950291, chr6:31950483-31950707, chr6:31950894-31950987, chr6:31951043-31951154, chr6:31951350-31951455, chr6:31951603-31951722, chr6:31951838-31951966, chr6:31952041-31952196, chr6:31958957-31959095, chr6:31959172-31959374, chr6:31959497-31959702, chr6:31960151-31960332, chr6:31960561-31960710, chr6:31960855-31960952, chr6:31961190-31961410, chr6:31965470-31965552, chr6:31966579-31966695, chr6:31966770-31966979, chr6:31967071-31967184, chr6:31967252-31967349, chr6:31969086-31969198, chr6:31969261-31969382, chr6:31969542-31969648, chr6:31969888-31970043, chr6:31970164-31970328, chr6:31962263-31962495, chr6:31963484-31963582, chr6:31963720-31963899, chr6:31963972-31964111, chr6:31964909-31965099

3. C4B: The following C4B hg19 coordinates have been excluded from this assay: chr6:31992550-31992758, chr6:32001555-32001680, chr6:31997331-31997586, chr6:31992235-31992440, chr6:31996458-31996637, chr6:31994217-31994351, chr6:31994419-31994512, chr6:31995455-31995529, chr6:31995608-31995720, chr6:31995833-31996065, chr6:31982611-31982698, chr6:31982808-31983029, chr6:31983221-31983445, chr6:31983632-31983725, chr6:31983781-31983892, chr6:31984088-31984193, chr6:31984341-31984460, chr6:31984576-31984704, chr6:31984779-31984934, chr6:31991695-31991833, chr6:31991910-31992112, chr6:31992889-31993070, chr6:31993299-31993448, chr6:31993593-31993690, chr6:31993928-31994148, chr6:31998207-31998289, chr6:31999316-31999432, chr6:31999507-31999716, chr6:31999808-31999921, chr6:31999989-32000086, chr6:32001823-32001935, chr6:32001998-32002119, chr6:32002279-32002385, chr6:32002625-32002780, chr6:32002901-32003065, chr6:31995001-31995233, chr6:31994748-31994910, chr6:31996222-31996320, chr6:31996710-31996849, chr6:31997646-31997836

4. CCDC40: The following CCDC40 hg19 coordinates have been excluded from this assay: chr17:78010450-78010501 5. CFHR1: The following CFHR1 hg19 coordinates have been excluded from this assay: chr1:196788963-196789043, chr1:196799618-

196799823 6. CFHR3: The following CFHR3 hg19 coordinates have been excluded from this assay: chr1:196759163-196759368 7. CORO1A: The following CORO1A hg19 coordinates have been excluded from this assay: chr16:30200169-30200296 8. CSF2RA: The following CSF2RA hg19 coordinates have been excluded from this assay: chrX:1422142-1422266 9. CYBB: The following CYBB hg19 coordinates have been excluded from this assay: chrX:37656945-37657156 10. DCLRE1C: The following DCLRE1C hg19 coordinates have been excluded from this assay: chr10:14966805-14967016 11. DUOX2: The following DUOX2 hg19 coordinates have been excluded from this assay: chr15:45403297-45403486 12. Excluded Regions 13. IKBKG: The following IKBKG hg19 coordinates have been excluded from this assay: chrX:153792522-153792687, chrX:153784368-

153784602, chrX:153786735-153786876, chrX:153788610-153788785, chrX:153791013-153791179, chrX:153792162-153792246, chrX:153791762-153791927, chrX:153789891-153790010

14. IRAK4: The following IRAK4 hg19 coordinates have been excluded from this assay: chr12:44178044-44178050



15. NCF1: The following NCF1 hg19 coordinates have been excluded from this assay: chr7:74203371-74203515, chr7:74202316-74202443, chr7:74199516-74199656, chr7:74197270-74197415, chr7:74191601-74191704, chr7:74197856-74197986, chr7:74193591-74193779, chr7:74202891-74203059, chr7:74193416-74193514, chr7:74195114-74195192, chr7:74188367-74188461

16. PMS2: The following PMS2 hg19 coordinates have been excluded from this assay: chr7:6026378-6027262, chr7:6017207-6017432, chr7:6022443-6022633, chr7:6013018-6013184

17. SLC37A4: The following SLC37A4 hg19 coordinates have been excluded from this assay: chr11:118901156-118901367 18. STAT5B: The following STAT5B hg19 coordinates have been excluded from this assay: chr17:40370729-40370907, chr17:40371318-

40371492, chr17:40371718-40371871



PRIMARY IMMUNODEFIENCY (PID) SUBPANEL Primary immunodeficiency diseases (PID) are comprised by more than 130 disorders rooted in genetic defects of at least a single gene (Kobrynski, et al 2014). PIDs first manifest through recurrent infections of variable frequencies beginning from a very young age, although some patients go undiagnosed due to the mild nature of the symptoms. Infections can be localized or systemic and commonly target various areas of the body such as the skin, mucosal membranes, ears, gastrointestinal tract, or more severely, the central nervous system. Infections in those with PID often present with greater severity, frequency, persistence, and/or are caused by opportunistic pathogens (Al-Herz, et al 2011). Patients with primary immunodeficiency diseases may also exhibit autoimmune symptoms including hypoparathyroidism, adrenocortical failure, hepatitis, primary biliary cirrhosis, thyroiditis, autoimmune hemolytic anemia, type 1 diabetes mellitus, vitiligo, keratoconjunctivitis, ectodermal dysplasia and others (Todoric, et al 2013). Due to the largely hereditary nature of primary immunodeficiency diseases, family members are often at elevated risk for symptoms. The Primary Immunodeficiency Subpanel includes the following 206 genes.


ACD 609377 Comprehensive Immunodeficiency; Primary Immunodeficiency

616553: AR, AD ?Dyskeratosis congenita, AD 6 616553: AR, AD ?Dyskeratosis congenita, AR 7 AD, AR

ACP5 171640 Comprehensive Immunodeficiency; Primary Immunodeficiency

607944: AR Spondyloenchondrodysplasia with immune dysregulation AR



AR

ADA2 607575 Comprehensive Immunodeficiency; Primary Immunodeficiency

615688: AR Polyarteritis nodosa, childhood-onset 182410: AR ?Sneddon syndrome AR

ADAR 146920 Comprehensive Immunodeficiency; Primary Immunodeficiency

615010: AR Aicardi-Goutieres syndrome 6 127400: AD Dyschromatosis symmetrica hereditaria AD, AR



AIRE 607358 Comprehensive Immunodeficiency; Primary Immunodeficiency

240300: AR, AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia

AD, AR

AK2 103020 Comprehensive Immunodeficiency; Primary Immunodeficiency; Severe Combined Immunodeficiency 267500: AR Reticular dysgenesis

AR

AP3B1 603401 Comprehensive Immunodeficiency; Primary Immunodeficiency 608233: AR Hermansky-Pudlak syndrome 2 AR

B2M 109700 Comprehensive Immunodeficiency; Primary Immunodeficiency

105200: AD ?Amyloidosis, familial visceral 241600: AR Immunodeficiency 43 AD, AR



XLR, XL

C1QA 120550 Comprehensive Immunodeficiency; Primary Immunodeficiency 613652: AR C1q deficiency AR

C1QB 120570 Comprehensive Immunodeficiency; Primary Immunodeficiency 613652: AR C1q deficiency AR

C1QC 120575 Comprehensive Immunodeficiency; Primary Immunodeficiency 613652: AR C1q deficiency AR

C1S 120580 Comprehensive Immunodeficiency; Primary Immunodeficiency

613783: C1s deficiency 617174: AD Ehlers-Danlos syndrome, periodontal type, 2

AD


217000: AR C2 deficiency 615489: {Macular degeneration, age-related, 14, reduced risk of}

AR

C4A 120810 Comprehensive Immunodeficiency; Primary Immunodeficiency

614374: [Blood group, Rodgers] 614380: AR C4a deficiency AR


609536: C5 deficiency 615749: AD [Eculizumab, poor response to] AD

C8B 120960 Comprehensive Immunodeficiency; Primary 613789: AR C8 deficiency, type II AR





613825: C9 deficiency 615591: {Macular degeneration, age-related, 15, susceptibility to}

None


616452: AD B-cell expansion with NFKB and T-cell anergy 615206: AR Immunodeficiency 11A 617638: AD Immunodeficiency 11B with atopic dermatitis

AD, AR


173200: AD Pityriasis rubra pilaris 602723: AD Psoriasis 2 AD

CARD9 607212 Comprehensive Immunodeficiency; Primary Immunodeficiency 212050: AR Candidiasis, familial, 2, AR AR


603909: AD Autoimmune lymphoproliferative syndrome, type II 613659: Gastric cancer, somatic 605027: Lymphoma, non-Hodgkin, somatic

AD


607271: AR ?Autoimmune lymphoproliferative syndrome, type IIB 114480: AD {Breast cancer, protection against} 114550: Hepatocellular carcinoma, somatic 211980: AR {Lung cancer, protection against}

AD, AR

CD19 107265 Comprehensive Immunodeficiency; Primary Immunodeficiency 613493: AR Immunodeficiency, common variable, 3 AR

CD247 186780 Comprehensive Immunodeficiency; Primary Immunodeficiency; Severe Combined Immunodeficiency 610163: AR ?Immunodeficiency 25

AR

CD27 186711 Comprehensive Immunodeficiency; Primary Immunodeficiency 615122: AR Lymphoproliferative syndrome 2 AR

CD3D 186790 Comprehensive Immunodeficiency; Primary Immunodeficiency; Severe Combined Immunodeficiency 615617: AR Immunodeficiency 19

AR


615615: AR Immunodeficiency 18 615615: AR Immunodeficiency 18, SCID variant

AR







612922: AR, AD {Hemolytic uremic syndrome, atypical, susceptibility to, 2} AD, AR


612300: AR Hemolytic anemia, CD59-mediated, with or without immune-mediated polyneuropathy AR

CD79A 112205 Comprehensive Immunodeficiency; Primary Immunodeficiency 613501: AR Agammaglobulinemia 3 AR

CD79B 147245 Comprehensive Immunodeficiency; Primary Immunodeficiency 612692: AR Agammaglobulinemia 6 AR

CD8A 186910 Comprehensive Immunodeficiency; Primary Immunodeficiency 608957: AR CD8 deficiency, familial AR

CEBPE 600749 Comprehensive Immunodeficiency; Primary Immunodeficiency 245480: AR Specific granule deficiency AR

CFD 134350 Comprehensive Immunodeficiency; Primary Immunodeficiency 613912: AR Complement factor D deficiency AR

CFH 134370 Comprehensive Immunodeficiency; Primary Immunodeficiency

126700: AD Basal laminar drusen 609814: AR, AD Complement factor H deficiency 235400: AR, AD {Hemolytic uremic syndrome, atypical, susceptibility to, 1} 610698: {Macular degeneration, age-related, 4}

AD, AR

CFI 217030 Comprehensive Immunodeficiency; Primary Immunodeficiency

610984: AR Complement factor I deficiency 612923: AD {Hemolytic uremic syndrome, atypical, susceptibility to, 3} 615439: AD {Macular degeneration, age-related,

AD, AR



Gene MIM Disease Category OMIM Phenotype Inheritance 13, susceptibility to}

CFP 300383 Comprehensive Immunodeficiency; Primary Immunodeficiency 312060: XLR Properdin deficiency, XL XLR, XL

CHD7 608892 Comprehensive Immunodeficiency; Primary Immunodeficiency

214800: AD CHARGE syndrome 612370: AD Hypogonadotropic hypogonadism 5 with or without anosmia

AD

CIITA 600005 Comprehensive Immunodeficiency; Primary Immunodeficiency

209920: AR Bare lymphocyte syndrome, type II, complementation group A 180300: {Rheumatoid arthritis, susceptibility to}

AR

CLPB 616254 Comprehensive Immunodeficiency; Primary Immunodeficiency

616271: AR 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia

AR

COPA 601924 Comprehensive Immunodeficiency; Primary Immunodeficiency

616414: AD {Autoimmune interstitial lung, joint, and kidney disease} AD

CORO1A 605000 Comprehensive Immunodeficiency; Primary Immunodeficiency; Severe Combined Immunodeficiency 615401: AR Immunodeficiency 8

AR

CR2 120650 Comprehensive Immunodeficiency; Primary Immunodeficiency

614699: AR Immunodeficiency, common variable, 7 610927: {Systemic lupus erythematosus, susceptibility to, 9}

AR

CSF2RA 306250 Comprehensive Immunodeficiency; Primary Immunodeficiency

300770: Surfactant metabolism dysfunction, pulmonary, 4 None

CSF3R 138971 Comprehensive Immunodeficiency; Primary Immunodeficiency 617014: AR Neutropenia, severe congenital, 7, AR AR

CTC1 613129 Comprehensive Immunodeficiency; Primary Immunodeficiency

612199: AR Cerebroretinal microangiopathy with calcifications and cysts AR

CTLA4 123890

Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease


AD

CTPS1 123860 Comprehensive Immunodeficiency; Primary Immunodeficiency 615897: AR Immunodeficiency 24 AR

CTSC 602365 Comprehensive Immunodeficiency; Primary Immunodeficiency

245010: AR Haim-Munk syndrome 245000: AR Papillon-Lefevre syndrome 170650: AR Periodontitis 1, juvenile

AR

CXCR4 162643 Comprehensive Immunodeficiency; Primary Immunodeficiency

Myelokathexis, isolated (3) 193670: AD WHIM syndrome AD





XLR, XL

DCLRE1B 609683 Comprehensive Immunodeficiency; Primary Immunodeficiency None None



AR

DGKE 601440 Comprehensive Immunodeficiency; Primary Immunodeficiency

615008: AR {Hemolytic uremic syndrome, atypical, susceptibility to, 7} 615008: AR Nephrotic syndrome, type 7

AR


DNMT3B 602900 Comprehensive Immunodeficiency; Primary Immunodeficiency


DOCK2 603122 Comprehensive Immunodeficiency; Primary Immunodeficiency 616433: AR Immunodeficiency 40 AR


243700: AR Hyper-IgE recurrent infection syndrome, AR

AR

ELANE 130130 Comprehensive Immunodeficiency; Primary 162800: AD Neutropenia, cyclic AD



Gene MIM Disease Category OMIM Phenotype Inheritance Immunodeficiency 202700: AD Neutropenia, severe congenital 1, AD

EPG5 615068 Comprehensive Immunodeficiency; Primary Immunodeficiency 242840: AR Vici syndrome AR

FADD 602457 Comprehensive Immunodeficiency; Primary Immunodeficiency

613759: AR Infections, recurrent, with encephalopathy, hepatic dysfunction, and cardiovascular malformations

AR

FAS 134637

Comprehensive Immunodeficiency; Primary Immunodeficiency

601859: AD Autoimmune lymphoproliferative syndrome, type IA 601859: AD {Autoimmune lymphoproliferative syndrome} Squamous cell carcinoma, burn scar-related, somatic (3)

AD

FASLG 134638 Comprehensive Immunodeficiency; Primary Immunodeficiency

601859: AD Autoimmune lymphoproliferative syndrome, type IB 211980: AR {Lung cancer, susceptibility to}

AD, AR

FCN1 601252 Comprehensive Immunodeficiency; Primary Immunodeficiency None None

FERMT3 607901 Comprehensive Immunodeficiency; Primary Immunodeficiency 612840: AR Leukocyte adhesion deficiency, type III AR


601705: AR T-cell immunodeficiency, congenital alopecia, and nail dystrophy

AR



AR, XLR, XL



G6PD 305900 Comprehensive Immunodeficiency; Primary Immunodeficiency

300908: XLD Hemolytic anemia, G6PD deficient (favism) 611162: {Resistance to malaria due to G6PD deficiency}

XLD

GATA2 137295


614038: AD Emberger syndrome 614172: AD Immunodeficiency 21 601626: AD {Leukemia, acute myeloid, susceptibility to} 614286: {Myelodysplastic syndrome, susceptibility to}

AD


146255: AD Hypoparathyroidism, sensorineural deafness, and renal dysplasia AD

GFI1 600871 Comprehensive Immunodeficiency; Primary Immunodeficiency

607847: AD ?Neutropenia, nonimmune chronic idiopathic, of adults 613107: AD ?Neutropenia, severe congenital 2, AD

AD

HAX1 605998 Comprehensive Immunodeficiency; Primary Immunodeficiency 610738: AR Neutropenia, severe congenital 3, AR AR


IFIH1 606951 Comprehensive Immunodeficiency; Primary Immunodeficiency

615846: AD Aicardi-Goutieres syndrome 7 182250: AD Singleton-Merten syndrome 1 AD

IFNGR1 107470


600263: {H. pylori infection, susceptibility to} 610424: {Hepatitis B virus infection, susceptibility to} 209950: AR Immunodeficiency 27A, mycobacteriosis, AR 615978: AD Immunodeficiency 27B, mycobacteriosis, AD 607948: {Tuberculosis infection, protection against} 607948: {Tuberculosis, susceptibility to}

AD, AR

IFNGR2 147569 Comprehensive Immunodeficiency; Primary Immunodeficiency 614889: AR Immunodeficiency 28, mycobacteriosis AR

IGHM 147020 Comprehensive Immunodeficiency; Primary Immunodeficiency 601495: AR Agammaglobulinemia 1 AR

IGLL1 146770 Comprehensive Immunodeficiency; Primary Immunodeficiency 613500: AR Agammaglobulinemia 2 AR




IKBKB 603258 Comprehensive Immunodeficiency; Primary Immunodeficiency 615592: AR Immunodeficiency 15 AR

IKBKG 300248


300291: Ectodermal dysplasia, hypohidrotic, with immune deficiency 300301: Ectodermal, dysplasia, anhidrotic, lymphedema and immunodeficiency 300636: XLR Immunodeficiency 33 300584: Immunodeficiency, isolated 308300: XLD Incontinentia pigmenti 300640: Invasive pneumococcal disease, recurrent isolated, 2

XLD, XLR

IL10 124092 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease

614395: {Graft-versus-host disease, protection against} 609423: {HIV-1, susceptibility to} 180300: {Rheumatoid arthritis, progression of}

None



IL12RB1 601604 Comprehensive Immunodeficiency; Primary Immunodeficiency 614891: AR Immunodeficiency 30 AR




AR



XLR, XL

IL36RN 605507 Comprehensive Immunodeficiency; Primary Immunodeficiency 614204: AR Psoriasis 14, pustular AR


608971: AR Severe combined immunodeficiency, T-cell negative, B-cell/natural killer cell-positive type

AR

INO80 610169 Comprehensive Immunodeficiency; Primary Immunodeficiency None None

IRAK4 606883 Comprehensive Immunodeficiency; Primary Immunodeficiency

607676: IRAK4 deficiency 610799: Invasive pneumococcal disease, recurrent isolated, 1

None

IRF7 605047 Comprehensive Immunodeficiency; Primary Immunodeficiency 616345: AR ?Immunodeficiency 39 AR

IRF8 601565 Comprehensive Immunodeficiency; Primary Immunodeficiency

614893: AD Immunodeficiency 32A, mycobacteriosis, AD 226990: AR Immunodeficiency 32B, monocyte and dendritic cell deficiency, AR

AD, AR

ISG15 147571 Comprehensive Immunodeficiency; Primary Immunodeficiency 616126: AR Immunodeficiency 38 AR

ITGAM 120980 Comprehensive Immunodeficiency; Primary Immunodeficiency

609939: {Systemic lupus erythematous, association with susceptibility to, 6} None


ITK 186973 Comprehensive Immunodeficiency; Primary Immunodeficiency 613011: AR Lymphoproliferative syndrome 1 AR

JAGN1 616012 Comprehensive Immunodeficiency; Primary Immunodeficiency 616022: AR Neutropenia, severe congenital, 6, AR AR

JAK1 147795 Comprehensive Immunodeficiency; Primary Immunodeficiency None None

JAK3 600173 Comprehensive Immunodeficiency; Primary Immunodeficiency; Severe Combined Immunodeficiency 600802: AR SCID, AR, T-negative/B-positive type

AR

LAMTOR2 610389 Comprehensive Immunodeficiency; Primary Immunodeficiency

610798: AR Immunodeficiency due to defect in MAPBP-interacting protein AR

LCK 153390 Comprehensive Immunodeficiency; Primary Immunodeficiency 615758: AR ?Immunodeficiency 22 AR





606593: AR LIG4 syndrome 254500: SM {Multiple myeloma, resistance to}

AR, SM

LPIN2 605519 Comprehensive Immunodeficiency; Primary Immunodeficiency 609628: Majeed syndrome None




MAGT1 300715 Comprehensive Immunodeficiency; Primary Immunodeficiency

300853: Immunodeficiency, XL, with magnesium defect, Epstein-Barr virus infection and neoplasia XL

MALT1 604860 Comprehensive Immunodeficiency; Primary Immunodeficiency 615468: AR Immunodeficiency 12 AR

MAP3K14 604655 Comprehensive Immunodeficiency; Primary Immunodeficiency None None

MASP2 605102 Comprehensive Immunodeficiency; Primary Immunodeficiency 613791: AR MASP2 deficiency AR





AD, AR

MYD88 602170 Comprehensive Immunodeficiency; Primary Immunodeficiency

153600: Macroglobulinemia, Waldenstrom, somatic 612260: Pyogenic bacterial infections, recurrent, due to MYD88 deficiency

None

NBN 602667 Comprehensive Immunodeficiency; Primary Immunodeficiency

609135: Aplastic anemia 613065: Leukemia, acute lymphoblastic 251260: AR Nijmegen breakage syndrome

AR





NFAT5 604708 Comprehensive Immunodeficiency; Primary Immunodeficiency None None

NFKB2 164012 Comprehensive Immunodeficiency; Primary Immunodeficiency

615577: AD Immunodeficiency, common variable, 10 AD

NFKBIA 164008 Comprehensive Immunodeficiency; Primary Immunodeficiency

612132: AD Ectodermal dysplasia, anhidrotic, with T-cell immunodeficiency AD



None

NHP2 606470 Comprehensive Immunodeficiency; Primary Immunodeficiency 613987: AR Dyskeratosis congenita, AR 2 AR



AD


611762: AD Familial cold autoinflammatory syndrome 2 AD

NLRP3 606416


607115: AD CINCA syndrome 617772: AD Deafness, AD 34, with or without inflammation 120100: AD Familial cold inflammatory syndrome 1 148200: AD Keratoendothelitis fugax hereditaria 191900: AD Muckle-Wells syndrome

AD



AD, MF

NOP10 606471 Comprehensive Immunodeficiency; Primary Immunodeficiency 224230: AR Dyskeratosis congenita, AR 1 AR

NRAS 164790 Comprehensive Immunodeficiency; Primary 114500: Colorectal cancer, somatic AD



Gene MIM Disease Category OMIM Phenotype Inheritance Immunodeficiency 162900: Epidermal nevus, somatic

137550: Melanocytic nevus syndrome, congenital, somatic 249400: Neurocutaneous melanosis, somatic 613224: AD Noonan syndrome 6 614470: ?RAS-associated autoimmune lymphoproliferative syndrome type IV, somatic 163200: Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic 188470: Thyroid carcinoma, follicular, somatic


612782: AR Immunodeficiency 9 615883: AD Myopathy, tubular aggregate, 2

AD, AR

PGM3 172100 Comprehensive Immunodeficiency; Primary Immunodeficiency 615816: AR Immunodeficiency 23 AR




AD, AR



AD

PNP 164050 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease; Severe Combined Immunodeficiency

613179: AR Immunodeficiency due to purine nucleoside phosphorylase deficiency

AR

POLE 174762 Comprehensive Immunodeficiency; Primary Immunodeficiency

615083: AD {Colorectal cancer, susceptibility to, 12} 615139: AR FILS syndrome AD, AR



AR

PRKCD 176977 Comprehensive Immunodeficiency; Primary Immunodeficiency

615559: AR Autoimmune lymphoproliferative syndrome, type III AR


615966: AR Immunodeficiency 26, with or without neurologic abnormalities

AR



AR

RAB27A 603868 Comprehensive Immunodeficiency; Primary Immunodeficiency 607624: AR Griscelli syndrome, type 2 AR

RAC2 602049 Comprehensive Immunodeficiency; Primary Immunodeficiency; Severe Combined Immunodeficiency 608203: Neutrophil immunodeficiency syndrome

None

RAG1 179615

Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease; Severe Combined Immunodeficiency


AR



AR

RBCK1 610924 Comprehensive Immunodeficiency; Primary Immunodeficiency

615895: AR Polyglucosan body myopathy 1 with or without immunodeficiency AR


209920: AR Bare lymphocyte syndrome, type II, complementation group C 209920: AR Bare lymphocyte syndrome, type II,

AR



Gene MIM Disease Category OMIM Phenotype Inheritance complementation group E





RHOH 602037 Comprehensive Immunodeficiency; Primary Immunodeficiency None None



AR

RNASEH2A 606034 Comprehensive Immunodeficiency; Primary Immunodeficiency 610333: AR Aicardi-Goutieres syndrome 4 AR

RNASEH2B 610326 Comprehensive Immunodeficiency; Primary Immunodeficiency 610181: AR Aicardi-Goutieres syndrome 2 AR

RNASEH2C 610330 Comprehensive Immunodeficiency; Primary Immunodeficiency 610329: AR Aicardi-Goutieres syndrome 3 AR

RORC 602943 Comprehensive Immunodeficiency; Primary Immunodeficiency 616622: AR Immunodeficiency 42 AR



AD, AR

SAMHD1 606754 Comprehensive Immunodeficiency; Primary Immunodeficiency

612952: AR Aicardi-Goutieres syndrome 5 614415: AD ?Chilblain lupus 2 AD, AR


SKIV2L 600478 Comprehensive Immunodeficiency; Primary Immunodeficiency 614602: AR Trichohepatoenteric syndrome 2 AR

SLC35C1 605881 Comprehensive Immunodeficiency; Primary Immunodeficiency

266265: AR Congenital disorder of glycosylation, type IIc AR



SMARCAL1 606622 Comprehensive Immunodeficiency; Primary Immunodeficiency 242900: AR Schimke immunoosseous dysplasia AR

SP110 604457 Comprehensive Immunodeficiency; Primary Immunodeficiency

235550: AR Hepatic venoocclusive disease with immunodeficiency 607948: {Mycobacterium tuberculosis, susceptibility to}

AR

SPINK5 605010 Comprehensive Immunodeficiency; Primary Immunodeficiency 256500: AR Netherton syndrome AR



AD, AR



AD



None



AD, AR

STK4 604965 Comprehensive Immunodeficiency; Primary Immunodeficiency

614868: T-cell immunodeficiency, recurrent infections, autoimmunity, and cardiac malformations

None



STXBP2 601717 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease


TAP1 170260 Comprehensive Immunodeficiency; Primary 604571: AR Bare lymphocyte syndrome, type I AR




TAP2 170261 Comprehensive Immunodeficiency; Primary Immunodeficiency

604571: AR Bare lymphocyte syndrome, type I, due to TAP2 deficiency AR

TAPBP 601962 Comprehensive Immunodeficiency; Primary Immunodeficiency 604571: AR Bare lymphocyte syndrome, type I AR

TAZ 300394 Comprehensive Immunodeficiency; Primary Immunodeficiency 302060: XLR Barth syndrome XLR



AD

TCN2 613441 Comprehensive Immunodeficiency; Primary Immunodeficiency 275350: AR Transcobalamin II deficiency AR

TERC 602322 Comprehensive Immunodeficiency; Primary Immunodeficiency

614743: AD {Aplastic anemia} 127550: AD Dyskeratosis congenita, AD 1 614743: AD {Pulmonary fibrosis, idiopathic, susceptibility to}

AD

TERT 187270


613989: AR, AD {Dyskeratosis congenita, AD 2} 613989: AR, AD {Dyskeratosis congenita, AR 4} 601626: AD {Leukemia, acute myeloid} 615134: {Melanoma, cutaneous malignant, 9} 614742: AD {Pulmonary fibrosis and/or bone marrow failure, telomere-related, 1}

AD, AR

TINF2 604319 Comprehensive Immunodeficiency; Primary Immunodeficiency

613990: AD Dyskeratosis congenita, AD 3 268130: AD Revesz syndrome AD

TLR3 603029 Comprehensive Immunodeficiency; Primary Immunodeficiency

613002: AR, AD {Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 2} 609423: {HIV1 infection, resistance to}

AD, AR

TMEM173 612374 Comprehensive Immunodeficiency; Primary Immunodeficiency

615934: AD STING-associated vasculopathy, infantile-onset AD

TNFAIP3 191163 Comprehensive Immunodeficiency; Primary Immunodeficiency

616744: AD Autoinflammatory syndrome, familial, Behcet-like AD

TNFRSF13B 604907 Comprehensive Immunodeficiency; Primary Immunodeficiency

240500: AR, AD Immunodeficiency, common variable, 2 609529: Immunoglobulin A deficiency 2

AD, AR

TNFRSF13C 606269 Comprehensive Immunodeficiency; Primary Immunodeficiency 613494: AR Immunodeficiency, common variable, 4 AR

TNFRSF1A 191190 Comprehensive Immunodeficiency; Primary Immunodeficiency

614810: {Multiple sclerosis, susceptibility to, 5} 142680: AD Periodic fever, familial AD

TNFSF12 602695 Comprehensive Immunodeficiency; Primary Immunodeficiency None None

TREX1 606609


225750: AR, AD Aicardi-Goutieres syndrome 1, dominant and recessive 610448: AD Chilblain lupus 152700: AD {Systemic lupus erythematosus, susceptibility to} 192315: AD Vasculopathy, retinal, with cerebral leukodystrophy

AD, AR

TRNT1 612907 Comprehensive Immunodeficiency; Primary Immunodeficiency

616959: AR Retinitis pigmentosa and erythrocytic microcytosis 616084: AR Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay

AR



TYK2 176941 Comprehensive Immunodeficiency; Primary Immunodeficiency 611521: AR Immunodeficiency 35 AR

UNC13D 608897 Comprehensive Immunodeficiency; Primary Immunodeficiency


UNG 191525 Comprehensive Immunodeficiency; Primary Immunodeficiency

608106: AR Immunodeficiency with hyper IgM, type 5 AR

USB1 613276 Comprehensive Immunodeficiency; Primary Immunodeficiency 604173: AR Poikiloderma with neutropenia AR

VPS13B 607817 Comprehensive Immunodeficiency; Primary 216550: AR Cohen syndrome AR




VPS45 610035 Comprehensive Immunodeficiency; Primary Immunodeficiency 615285: AR Neutropenia, severe congenital, 5, AR AR



XLR, XL

WIPF1 602357 Comprehensive Immunodeficiency; Primary Immunodeficiency 614493: ?Wiskott-Aldrich syndrome 2 None

WRAP53 612661 Comprehensive Immunodeficiency; Primary Immunodeficiency 613988: AR Dyskeratosis congenita, AR 3 AR




AR

ZBTB24 614064 Comprehensive Immunodeficiency; Primary Immunodeficiency



Note: somatic mutations are not reported); XL (X-linked); XLD (X-linked Dominant); and XLR (X-linked Recessive). 2. C4A: The following C4A hg19 coordinates have been excluded from this assay: chr6:31959812-31960020, chr6:31962010-31962172,

chr6:31968818-31968943, chr6:31964594-31964849, chr6:31961479-31961613, chr6:31961681-31961774, chr6:31962717-31962791, chr6:31962870-31962982, chr6:31963095-31963327, chr6:31949873-31949960, chr6:31950070-31950291, chr6:31950483-31950707, chr6:31950894-31950987, chr6:31951043-31951154, chr6:31951350-31951455, chr6:31951603-31951722, chr6:31951838-31951966, chr6:31952041-31952196, chr6:31958957-31959095, chr6:31959172-31959374, chr6:31959497-31959702, chr6:31960151-31960332, chr6:31960561-31960710, chr6:31960855-31960952, chr6:31961190-31961410, chr6:31965470-31965552, chr6:31966579-31966695, chr6:31966770-31966979, chr6:31967071-31967184, chr6:31967252-31967349, chr6:31969086-31969198, chr6:31969261-31969382, chr6:31969542-31969648, chr6:31969888-31970043, chr6:31970164-31970328, chr6:31962263-31962495, chr6:31963484-31963582, chr6:31963720-31963899, chr6:31963972-31964111, and chr6:31964909-31965099

3. CORO1A: The following CORO1A hg19 coordinates have been excluded from this assay: chr16:30200169-30200296 4. CSFR2A: The following CSFR2A hg19 coordinates have been excluded from this assay: chrX:1422142-1422266 5. CYBB: The following CYBB hg19 coordinates have been excluded from this assay: chrX:37656945-37657156 6. DCLRE1C: The following DCLRE1C hg19 coordinates have been excluded from this assay: chr10:14966805-14967016 7. IKBKG: The following IKBKG hg19 coordinates have been excluded from this assay: chrX:153792522-153792687, chrX:153784368-

153784602, chrX:153786735-153786876, chrX:153788610-153788785, chrX:153791013-153791179, chrX:153792162-153792246, chrX:153791762-153791927, and chrX:153789891-153790010

8. IRAK4: The following IRAK4 hg19 coordinates have been excluded from this assay: chr12:44178044-44178050 9. SLC37A4: The following SLC37A4 hg19 coordinates have been excluded from this assay: chr11:118901156-118901367 10. STAT5B: The following STAT5B hg19 coordinates have been excluded from this assay: chr17:40370729-40370907, chr17:40371318-

40371492, and chr17:40371718-40371871 11. TBX1: The following TBX1 hg19 coordinates have been excluded from this assay: chr22:19748416-19748814



INFLAMMATORY BOWEL DISEASE (IBD) SUBPANEL Inflammatory bowel disease (IBD) is comprised of ulcerative colitis, Crohn’s disease and unclassified IBD (IBDU). Despite the environmental factors recognized to contribute to pathology, concordance between monozygotic twins is significantly higher than that in dizygotic twins suggesting a significant genetic contribution (Thompson, et al 1996). The main symptoms share a high degree of similarity and may include diarrhea, abdominal pain, weight loss, bloody stool, fever, fatigue, and reduced appetite. However, ulcerative colitis is confined to the colon while Crohn’s Disease can be a multi-organ disorder, affecting the entire gastrointestinal tract and sometimes exhibiting involvement from the eyes, live, joints, etc. Diagnosis may occur at any stage in life although most symptoms develop before 30 years old. IBD is more highly prevalant amongst Ashkenazi Jews. Mendelian forms of IBD are a diagnostic challenge due to spectrum of 50+ conditions that can be present with IBD. Therefore genomic diagnosis offers opportunity for personalized care. The IBD Panel includes the following 59 genes known to be associated with or directly causative of the disease and its symptoms.




AR

ADAM17 603639 Comprehensive Immunodeficiency; Inflammatory Bowel Disease

614328: AR ?Inflammatory skin and bowel disease, neonatal, 1 AR





XLR, XL




CTLA4 123890 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease


AD





XLR, XL



AR






AR, XLR, XL




IL10 124092 Comprehensive Immunodeficiency; Primary 614395: {Graft-versus-host disease, protection None



Gene MIM Disease Category OMIM Phenotype Inheritance Immunodeficiency; Inflammatory Bowel Disease against}

609423: {HIV-1, susceptibility to} 180300: {Rheumatoid arthritis, progression of}



IL10RB 123889 Comprehensive Immunodeficiency; Inflammatory Bowel Disease

610424: {Hepatitis B virus, susceptibility to} 612567: AR Inflammatory bowel disease 25, early onset, AR

AR


IL21 605384 Comprehensive Immunodeficiency; Inflammatory Bowel Disease

615767: AR ?Immunodeficiency, common variable, 11 AR

IL23R 607562 Comprehensive Immunodeficiency; Inflammatory Bowel Disease

612261: {Inflammatory bowel disease 17, protection against} 605606: {Psoriasis, protection against}

None



AR



XLR, XL


608971: AR Severe combined immunodeficiency, T-cell negative, B-cell/natural killer cell-positive type AR











AD, AR







None



AD



AD, MF






AD, AR






AD

PNP 164050 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease; Severe Combined Immunodeficiency




AR





AR



AR



AR


209920: AR Bare lymphocyte syndrome, type II, complementation group C 209920: AR Bare lymphocyte syndrome, type II, complementation group E

AR







AD, AR






AD, AR



AD



STXBP2 601717 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel Disease






XLR, XL







AR


Note: somatic mutations are not reported); XL (X-linked); XLD (X-linked Dominant); and XLR (X-linked Recessive). 2. CYBB: The following CYBB hg19 coordinates have been excluded from this assay: chrX:37656945-37657156 3. DCLRE1C: The following DCLRE1C hg19 coordinates have been excluded from this assay: chr10:14966805-14967016 4. SLC37A4: The following SLC37A4 hg19 coordinates have been excluded from this assay: chr11:118901156-118901367



SEVERE COMBINED IMMUNODEFICIENCY (SCID) SUBPANEL Severe Combined Immunodeficiency Disorder (SCID) is the most severe manifestation of the primary immunodeficiency disorders and can be caused by deleterious mutations in many of the genes responsible for proper development of the immune cascade (Cossu, 2010). Affecting 1 in 40-75k newborns in the US, SCID is often referred to as the “Bubble Boy Disease” due to the first properly-documented patient being confined to a small sterile environment. However, moniker aside, not all patients exhibit total immunosuppression. SCID is a rare disease, with incidence rates estimated at 1 in 40-100,000 live births. SCID can be transmitted via various modes of inheritance including X-linked transmission (Yee, et al 2008). Despite the severity, SCID is clinically actionable, with patients requiring early defense from pathogens and a bone marrow transplant ideally in the first 3 months of life. Because of this, fast and accurate diagnosis is crucial to clinical outcome (Yee, et al 2008). The SCID Subpanel includes the following 26 genes to detect most common forms of SCID:




AR

AK2 103020 Comprehensive Immunodeficiency; Primary Immunodeficiency; Severe Combined Immunodeficiency

267500: AR Reticular dysgenesis AR

CD247 186780 Comprehensive Immunodeficiency; Primary Immunodeficiency; Severe Combined Immunodeficiency

610163: AR ?Immunodeficiency 25 AR

CD3D 186790 Comprehensive Immunodeficiency; Primary Immunodeficiency; Severe Combined Immunodeficiency



615615: AR Immunodeficiency 18 615615: AR Immunodeficiency 18, SCID variant

AR

CORO1A 605000 Comprehensive Immunodeficiency; Primary Immunodeficiency; Severe Combined Immunodeficiency




AR




601705: AR T-cell immunodeficiency, congenital alopecia, and nail dystrophy AR



XLR, XL


608971: AR Severe combined immunodeficiency, T-cell negative, B-cell/natural killer cell-positive type

AR

JAK3 600173 Comprehensive Immunodeficiency; Primary Immunodeficiency; Severe Combined Immunodeficiency

600802: AR SCID, AR, T-negative/B-positive type AR





None



PNP 164050 Comprehensive Immunodeficiency; Primary Immunodeficiency; Inflammatory Bowel




Gene MIM Disease Category OMIM Phenotype Inheritance Disease; Severe Combined Immunodeficiency





AR

RAC2 602049 Comprehensive Immunodeficiency; Primary Immunodeficiency; Severe Combined Immunodeficiency

608203: Neutrophil immunodeficiency syndrome None



AR



AR



AR



None



AD, AR



AD



AR


Note: somatic mutations are not reported); XL (X-linked); XLD (X-linked Dominant); and XLR (X-linked Recessive). 2. CORO1A: The following CORO1A hg19 coordinates have been excluded from this assay: chr16:30200169-30200296 3. DCLRE1C: The following DCLRE1C hg19 coordinates have been excluded from this assay: chr10:14966805-14967016 4. STAT5B: The following STAT5B hg19 coordinates have been excluded from this assay: chr17:40370729-40370907, chr17:40371318-

40371492, and chr17:40371718-40371871 5. TBX1: The following TBX1 hg19 coordinates have been excluded from this assay: chr22:19748416-19748814



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Disclaimer This test was developed and its performance characteristics were determined by Mount Sinai Genomics, Inc. DBA Sema4 and was considered acceptable for patient testing. It has not been cleared or approved by the FDA. The FDA has determined that such clearance or approval is not necessary. This type of mutation analysis generally provides highly accurate genotype information for microdeletions and microduplications. Despite this level of accuracy, it should be kept in mind that there are many potential sources of diagnostic error, including misidentification of samples, rare polymorphisms, or other rare genetic variants that interfere with analysis. In addition, families should understand the limitations of the testing and that rare diagnostic errors may occur for the reasons described.

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