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39th National Conference on Pediatric Health Care
©2018
March 19-22, 2018 CHICAGO
Integrating Genetics and Genomics into Practice
Stephanie J. Offord, FNP‐BC, AGN‐BC, MSNGina Lewis, CPNP‐PC, MSN
Interactive questions in presentation. To participate pleasetext NPGENETICS123 to 22333 once to join
©2018
DISCLOSURE
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Question 1
A father who has an X‐linked recessive disorder and a wife with a normal genotype will…
A. Pass the carrier state to his male children
B. Pass the carrier state to all of his children
C. Pass the carrier state to his female children
D. Not pass on the genetic mutation to any of his children
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Question 2
Exchange of segments between non homologous chromosomes is called:
A. Crossing over
B. Inversion
C. Duplication
D. Translocation
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Question 3
While assessing a client, the nurse notes that the client has numerous freckles on his skin. The nurse interprets this finding as which of the following?
A. Genotype
B. Genome
C. Variable expression
D. Phenotype
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Question 4
The nurse is working with a mother whose unborn child was diagnosed as having Down syndrome. The nurse explains to the mother that Down syndrome occurs due to which of the following?
A. Germ‐line mutation
B. Structural gene mutation
C. Chromosome nondisjunction
D. Phenotype nondisjunction
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Question 5
In Down’s syndrome, the chromosome number in each cell is:
A. 45
B. 46
C. 47
D. 48
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Objectives• Why Genetics is relevant in Medicine
– State of Genetics
– Children’s Hospital of WI clinic model
• Genetics relevance for all Nurse Practitioners
• The ABCs of Genetics
– Central dogma of genetics
– Basics of genetic testing
– Inheritance Patterns and Pedigrees
• Genetics referrals and resources
• Case Studies
• Future of Genetics
– Direct to Consumer Testing
– Pharmacogenomics
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Why is Genetics Relevant?
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Genetics in MedicinePreventionDiagnosis
Treatment
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Former President Obama announced “Precision Medicine” Initiative
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Precision Medicine
“An emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person”
NIH Precision Medicine Initiative
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Genetics vs Genomics
Genetics refers to the study of singlegenes and inherited characteristics
Genomics is the study of the function and combined influence of all genetic
sequences
World Health Organization, 2015 ©2018
State of Genetics
Critical Shortage
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Who are Geneticists and Genetic Counselors?
• Geneticist –Board certified physician in Genetics
• Genetic counselor –Master of Science in Genetic Counseling
–Genetic counselors receive special training in two areas ‐ genetics and counseling
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Children’s Hospital of WisconsinGenetics Model
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How does this impact you as an NP
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Genetics in Practice
Heme/Onc
Cardiology
Pharma
Neurology
GI Renal
Pulm
Rheum
Infectious Disease
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Lack of Genetic Training
Studies over the last 15 years showed little change in the knowledge levels of nurses in genetics and genomics.
Journal for Nurses in Professional Development 2017
“No discipline has evolved more quickly than genomics, and… so many nurses and NPs report feeling ill‐prepared to engage because they believe their baseline preparation and knowledge is weak.”
The Nurse Practitioner 2014
©2018
Objectives• Why Genetics is relevant in Medicine
– State of Genetics
– Children’s Hospital of WI clinic model
• Genetics relevance for all Nurse Practitioners
• The ABCs of Genetics
– Central dogma of genetics
– Basics of genetic testing
– Inheritance Patterns and Pedigrees
• Genetics referrals and resources
• Case Studies
• Future of Genetics
– Direct to Consumer Testing
– Pharmacogenomics
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DNA RNA Proteins
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Genetic Testing
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Review of Genetic Testing Types
• Karyotype
• FISH
• Chromosomal Microarray (CMA)
• Single Gene Testing
• Multigene panels
• Whole Exome Sequencing (WES)
• Whole Genome Sequencing (WGS)
• Non‐invasive Prenatal Screening (NIPS via cfDNA)
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Karyotype (Chromosome Analysis)
• Detects numerical chromosomal differences
• Detects large chromosomal rearrangements©2018
Fluorescence In Situ Hybridization (FISH)
• Quicker detection of numerical chromosomal differences
• Utilizes Probes to detect small changes
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Possible Chromosomal Variations
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Chromosome Variations
• May Involve:–Changing the structure of a chromosome
–The loss or gain of part of a chromosome
• Types of Variations–Deletion–Duplication– Inversion–Translocation–Nondisjunction
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Deletion
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Duplication
Occurs when a gene sequence is repeated
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Inversion
Occurs when a part of a chromosome is flipped upside down
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Translocation
• Involves two chromosomes that aren’t homologous
• Part of one chromosome is transferred to another chromosome
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Nondisjunction
Failure of chromosomes to separate during meiosis
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Trisomy 21 or Down syndrome
http://worms.zoology.wisc.edu/zooweb/Phelps/47XY_21.html
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Question 4
• The nurse is working with a mother whose unborn child was diagnosed as having Down syndrome. The nurse explains to the mother that Down syndrome occurs due to which of the following?
A. Germ‐line mutation
B. Structural gene mutation
C. Chromosome nondisjunction
D. Phenotype nondisjunction
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Chromosome Microarray
Detects deletions and duplications
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Possible Results• Pathogenic
– Disease‐causing
– The copy number variant identified is known to cause a genetic condition
• Benign– Harmless
– The copy number variant does not cause disease
• Variant of Uncertain Significance – Copy number variants with too little data to classify as either pathogenic or benign
– It is unknown whether this copy number variant causes a medical condition
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Why is a microarray important?
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Single Gene Testing
Single genes can be tested with a variety of methodologies
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Multigene Panel
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Exome vs Genome Sequencing
Whole exome sequencing scans all of the EXONS of all genes looking for DNA variants
Whole genome sequencing scans ALL of the genetic code
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Prenatal screen that utilizes fetal DNA circulating in maternal blood from placental cells
Cell‐Free Fetal DNA
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Inheritance Patterns and Pedigrees
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Autosomal Dominant Inheritance
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Autosomal Recessive Inheritance
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X‐Linked Recessive Inheritance
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Mitochondrial Inheritance
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Objectives• Why Genetics is relevant in Medicine
– State of Genetics
– Children’s Hospital of WI clinic model
• Genetics relevance for all Nurse Practitioners
• The ABCs of Genetics
– Central dogma of genetics
– Basics of genetic testing
– Inheritance Patterns and Pedigrees
• Genetics referrals and resources
• Case Studies
• Future of Genetics
– Direct to Consumer Testing
– Pharmacogenomics
11
©2018
Reasons for a Genetics referral
• Multiple congenital anomalies
• Developmental delay
• Autism
• Dysmorphic facial features
• Unusual growth pattern
– Overgrowth, short stature, or hemihyperplasia
• Family History
– Consanguinity
– Cognitive delays, developmental disability, inherited disorder, birth defects, or early deaths
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Genetics Resources
• GeneReviews– www.genereviews.org
• Online Mendelian Inheritance in Man (OMIM)–https://omim.org/
• Genetic and Rare Diseases Information Center (GARD) –https://rarediseases.info.nih.gov/
• Genetics Home Reference–https://ghr.nlm.nih.gov/
• Unique– www.rarechromo.org
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Genetics Facilities
• National Society of Genetic Counselors–www.nsgc.org
–www.findageneticcounselor.com
• American College of Medical Genetics
–www.acmg.net/ACMG/Find_Genetic_Services/ACMG/ISGweb/FindaGeneticService.aspx
• Genetic Testing–https://www.concertgenetics.com/
©2018
Objectives• Why Genetics is relevant in Medicine
– State of Genetics
– Children’s Hospital of WI clinic model
• Genetics relevance for all Nurse Practitioners
• The ABCs of Genetics
– Central dogma of genetics
– Basics of genetic testing
– Inheritance Patterns and Pedigrees
• Genetics referrals and resources
• Case Studies
• Future of Genetics
– Direct to Consumer Testing
– Pharmacogenomics
©2018
Case Study #1
16 y/o male referred by our IR dept for
• Arteriovenous malformation on L lower extremity
• Chronic pain
• Congenital cataracts
• R retinal detachment
• Asthma
• Anxiety, ADHD, and learning difficulties
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Pedigree
2
P
Thyroid abnormality
Macrocephaly
LD
AVM
Key
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Physical ExamHeight: 61% (177.6 cm) Weight: 47% (73.1 kg)HC: >98% (62 cm)
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PTEN hamartoma tumor syndrome
• Cowden syndrome (CS)
• Bannayan‐Riley‐Ruvalcaba syndrome (BRRS)
• PTEN‐related Proteus syndrome (PS)
• Proteus‐like syndrome
• PTEN pathogenic variant
–Designated c.493G>T
–previously reported in individuals with Cowden syndrome
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Cowden Syndrome
• Multiple hamartoma syndrome with a high risk for benign and malignant tumors of the thyroid, breast, and endometrium.
• Lifetime risk for cancer:
–85% breast
–35% epithelial thyroid (median age of 37)
–28% endometrial (starting in late 30s ‐ early 40s)
–9% colorectal (late 30s)
–35% renal cell carcinoma (late 40s)
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Management
• Pediatric–Annual thyroid US
–Annual skin check with PE
• Adult–Annual thyroid US and skin eval
–Women starting at 30 years:• Monthly self‐breast exams
• Yearly mammograms (MRI may be incorporated)
• Yearly transvaginal US or endometrial biopsy
– For men and women:• Colonoscopy at 35 years, frequency based on polyposis• Biennial renal imaging (CT or MRI) at 40 years
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Case Study #2
• 5 year old male referred to genetics for multiple café au lait macules (CALs)
• Also has a history of: –Speech delay
–Short stature
–Joint hypermobility
–Relative macrocephaly
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Pedigree
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Physical Exam Pertinent Positives
General Height 6%Weight 5%
Head Relative Macrocephaly (HC: 60%)2 hair whorls
Eyes Telencanthus
Ears Posteriorly rotated
Nose Broad nasal bridge
Skin Over 20 café au lait maculesNo axillary or inguinal freckling
Musculoskeletal Hypermobility of small and large joints
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Neurofibromatosis (NF1) Criteria
Must have 2 of the following:
• 6 or more cafe au lait spots measuring >5mm in diameter in a pre pubertal patient or >15mm in post pubertal patient
• 2 or more Lisch nodules
• 2 or more neurofibromas
• Tumor of the optic nerve pathway
• Osseous lesion
• Axillary and/or inguinal freckling
• Family history of NF1
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Pics of NF1 findings…
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Genetic Testing
• RASopathy Panel–Panel included 18 genes associated with RASopathies
–Identified pathogenic variant confirming NF1
• All other genes were negative
• Known familial variant testing was offered to 3 siblings and parents
–Identified NF1 variant in father and two other siblings
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Management Guidelines
Management guidelines:
• Yearly follow up including close monitoring of BP for evidence of hypertension
• Annual ophtho exams until age 10
• Developmental assessments to assess learning concerns
• Increased risk of breast cancer so we discuss early SBE
©2018
Objectives• Why Genetics is relevant in Medicine
– State of Genetics
– Children’s Hospital of WI clinic model
• Genetics relevance for all Nurse Practitioners
• The ABCs of Genetics
– Central dogma of genetics
– Basics of genetic testing
– Inheritance Patterns and Pedigrees
• Genetics referrals and resources
• Case Studies
• Future of Genetics
– Direct to Consumer Testing
– Pharmacogenomics
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Direct to Consumer Testing
©2018
Direct to Consumer Testing• Companies that sell genetic testing directly to a patient independent of their physician
• Can inform on medical conditions accidentally or give false reassurance
• This is not full gene sequencing
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Direct to Consumer Testing• “Biocompatibility Testing”
–HLA Testing
• “Neurocompatibility Testing”
–Serotonin Transporter
• “Psychological Compatibility”
–Questionnaire
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Direct to Consumer Testing
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What’s the harm?• What can it tell me about my health?
–Nothing!!!
• This is not full testing
• Can offer “false” reassurance
• Cannot take test results to a provider for interpretation.
Pharmacogenomics
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Pharmacogenomics
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Pharmacogenomics
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Limitations of Pharmacogenomics
• One single pharmacogenetic test cannot be used to determine response to all medications
– One medication in one pathway
– Only available for a small subset of medications
• Reimbursement for testing and counseling is limited
• Field of pharmacogenomics is still in its infancy
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The target = $1000 Genome
Next Generation Sequencing
In 1999, 200 of these were initiated to blast sequence the human genome
ABI 3730
700‐1000 bp reads1.2 Mb per day$0.50 per kilobase
capable of generating 2 TB under 2 days
That equates to approximately 720,000 ABI 3730 machines
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Potential Risks and Discomforts• Whole Exome Sequencing is NOT a perfect test
• It cannot identify the underlying causes of all genetic disease.
• Testing of other family members may reveal information regarding family relationships– i.e. non‐paternity or consanguinity
• There is a risk that you will learn genetic information about yourself or your family that is not directly related to the reason for ordering the test. – Incidental Findings
©2018
Incidental Findings• This is the risk that you will learn genetic information about your child that is
not directly related to your child’s current symptoms• Untreatable Childhood Disorders
– Conditions that do not explain your child’s current medical concerns but may present in the future
– This would be for information‐only, as no treatment exists
• Treatable Adulthood Disorders (medically actionable) –– The report may contain results in genes that are not related to the symptoms for which the test was ordered but that are medically actionable
– Medically actionable refers to a disease that a therapy or prevention exists to treat it.
• Untreatable Adulthood Disorders• Carrier Status – informative for future family planning
– Carrier status for autosomal recessive conditions that are recommended by ACMG or ACOG
You need to decide which of the above types of results you’d like to receive
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X Inactivation
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Penetrance and Expressivity