Genetic Kidney Diseases October 2001. Part I Genetics Resources Specific Diseases –Nail Patella Syndrome –Cystic disorders Medullary Cystic Kidney Disease

Genetic Kidney Diseases

October 2001

Part I• Genetics• Resources• Specific Diseases

– Nail Patella Syndrome– Cystic disorders

• Medullary Cystic Kidney Disease• Nephronopthisis• ADPKD• ARPKD

Genetics Part II 10/23/01

• Lowe Syndrome

• Fabry disease

• Cystinosis

• Cystinuria

• Hyperoxaluria

• Alports

Imagine this…•You are wrapping up the ER visit for your 15 year-old patient, Jay. You have addressed his

– dysuria – risk of recurrence– follow up visit

•Time is up.

•As Jay’s mother stands up to leave, she says, “By the way, my husband has just been diagnosed with colon cancer and his doctors are suggesting it is FAP. I heard there is a genetic test for FAP. Should our son be tested?”

copyright©1999copyright©1999Children’s Health Care SystemChildren’s Health Care System

What are the questions that pertain to genetic testing?

• What kind of genetic test is it?

• How would the genetic test be used?

• Would the genetic test help or hurt my patient?

• How is the genetic test applied in this situation?

• Where can I find a lab that does the test?

• What is involved in ordering this genetic test?

• How would a genetics consultation help?copyright©1999copyright©1999Children’s Health Care SystemChildren’s Health Care System

• Clinical testing - Done for the purpose of prevention, diagnosis, or treatment as part of patient care. Results are reported to the provider.

• Research testing - Done for the purpose of understanding a condition better, or developing a clinical test. Results are usually not provided.

Clinical vs. Research Testing


Three kinds of genetic tests

• Cytogenetic

• DNA

• Metabolic


KaryotypeKaryotype









• How would a genetics consultation help?


Genetic Testing isContext Specific

• Why are you testing THIS patient at THIS time?


Uses of Genetic Testing

• Diagnostic

• Predictive

• Carrier

• Prenatal

• Newborn Screening


FAP 10 y10 y

d. 35 y d. 35 y MVAMVA

63 y63 y

39 y39 y 33 y33 y 28 y28 y

6 y6 y14 y14 y









• How would a genetics consultation help?


Resources

• Medline

• OMIM (www.ncbi.nlm.nih.gov/)

• Genetests.org

• Geneclinics.org

• Genetics consult

Genetic CounselingGenetic CounselingMode of InheritanceMode of Inheritance• FAP is inherited in an autosomal dominant manner.FAP is inherited in an autosomal dominant manner.

Risk to Family MembersRisk to Family Members

Parents. Parents. Approximately 75-80% of individuals with FAP have Approximately 75-80% of individuals with FAP have an affected parent.an affected parent.

Siblings. Siblings. If neither parent meets the clinical diagnostic criteria If neither parent meets the clinical diagnostic criteria for FAP, the risk to the siblings of an affected individual is low.for FAP, the risk to the siblings of an affected individual is low.

Offspring. Offspring. Affected individuals have a 50% chance of Affected individuals have a 50% chance of transmitting the mutant gene to each child.transmitting the mutant gene to each child.


Would genetic testing help my patient?

• Reduces morbidity and mortality through close surveillance of high-risk individuals

• Eliminates need for extra surveillance in individuals with no increased risk


Would genetic testing hurt my patient?

• Psychological impact of knowing you have a life-threatening condition (or that you have escaped it)

• Possible insurance discrimination associated with high cancer risk

• Family discord because other members are at risk










Molecular DiagnosisMolecular Diagnosis

Two types of DNA-based tests are available clinically: protein Two types of DNA-based tests are available clinically: protein truncation testing (PTT) and linkage analysis.truncation testing (PTT) and linkage analysis.

If PTT testing is negative, linkage testing can be considered in If PTT testing is negative, linkage testing can be considered in families with more than one affected family member.families with more than one affected family member.

copyright©1999copyright©1999Children’s Health Care Children’s Health Care SystemSystem

Testing Strategy

P os it iveD irec t tes tin g ava ilab le

P roceed w ith tes tin g fam ily m em b ersTes tin g is h ig h ly accu ra te

N eg a tiveD irec t tes tin g n o t u se fu l

L in kag e tes tin g m ay b e h e lp fu lL in kag e is less accu ra te

Tes t D ad8 0 % p os it ive2 0 % n eg a tive











• Directory of Medical Genetics Laboratories

• Directory of Genetics Clinics and • Prenatal Diagnosis Clinics• Educational materials about • Genetic Counseling and Testing

• Requires one-time registration

• Free service

www.genetests.orgwww.genetests.org











PRETEST COUNSELING AND INFORMED CONSENT

Addressing:

• Risk perception, expectations and support systems. • Implications of testing vs. not testing.• Methods used to obtain specimens and associated risks. • Test accuracy (sensitivity and specificity). • The chance that the test will be positive. • Any out-of-pocket costs to the patient. • A plan for conveying test results. • Level of confidentiality.


SAMPLE LOGISTICS AND SUPPORTING DOCUMENTATION

What are the sample requirements?

Are samples from other family members needed? What specimen type is needed? Does the specimen need to be cultured before shipping? What is the requested amount of specimen? What information should be included on the label?


SAMPLE LOGISTICS AND SUPPORTING DOCUMENTATION

What supporting documentation is needed?

Does the lab have a specific requisition form? What clinical history should be included? Are medical records or test results on family members

needed? Is family history needed for test interpretation? (Pedigree) Is ethnicity relevant to test interpretation?


For Positive Test Results

If the Test The Interpretation Is… And Follow-up IncludesPurpose Was.. Genetic Counseling and...

Predictive Testing The likelihood of showing Life planning; symptoms is increased Medical Management










• Should we be tested for FAP?

• What is FAP?

• How does FAP affect health and well-being?

• What causes FAP?

• Who else in the family could get FAP?

• How can we cope with FAP?


What is the Family Really Asking?What is the Family Really Asking?

ABOUT GENETIC SERVICES

WHAT IS A GENETICS CONSULTATION?

A genetics consultation involves evaluation of an individual or family for one or more of the following:

Confirming, diagnosing or ruling out a genetic condition Identifying and arranging for medical management issues Calculating and communicating genetic risks Providing or arranging for psychosocial support


Cost of genetic services• Consultation $50-300

• Cytogenetic testing $500-600

• DNA-based testing $150-3000

• Third party coverage varies

• Lack of coverage may reflect misunderstanding or lack of information


Part I• Genetics

• Resources

• Specific Diseases– Nail Patella Syndrome

– Cystic disorders

• Medullary Cystic Kidney Disease

• Nephronopthisis

• ADPKD

• ARPKD

Nail Patella Syndrome(Hereditary osteo-onychodysplasia)

• Inheritance– Autosomal Dominant - loci 9q34.1– Counseling: patient w/ disorder and family hx w/ renal

involvement: proband disease risk is 1 in 4 and ESRD risk is 1 in 10

• Frequency - 22 per million

• Defect: LIM-homeodomain protein Lmx 1b – Skeletal defects– Specific form of renal dysplasia

Nail Patella Syndrome

Clinical Synopsis

– Hypoplastic or absent patella (90%)

– Dystrophic nails (98%)

– Elbow deformities (90%)

– Iliac horns (80%)

– Lester’s sign = heterochromia of iris (50%)

– Renal disease (50%) Hematuria (33%) ; proteinuria (42%); ESRD (10-23%)

NPS Nephropathology– GBM multiple mottled and lucent rarefactions “moth eaten”

appearance

– EM coarse fibrils, cross-banded collagen

– Basement Membranes variable thickening

– Foot process effacement

– Tubulointerstitial fibrosis

– IF: No deposits

– Glomeruli: normal or focal sclerosis

– Occasional: anti-GBM disease w/ cresecents


EM: glomerular basement membrane thickening with focal, irregular internal lucencies.Brenner & Rector's The Kidney, 6th ed


Banded collagen fibrils within the rarefied segments of GBMBrenner & Rector's The Kidney, 6th ed

Medullary Cystic Kidney Ds. & Nephronopthisis

Similarities

• Clinical symptoms– Polyuria, polydypsia, anemia, bland urine

• Macroscopic pathology– Corticomedullary junction cysts– Normal renal size

• Renal histology– TBM disintegration– Tubular atrophy w/ cyst formation– Interstitial fibrosis and infiltration

MCKD-NPHDistinctive Features

• Age of onset

• Inheritance pattern

• Genetic loci

• Extrarenal manifestations

Medullary Cystic Disease

MCKD1 MCKD2

Inheritance AD AD

Loci 1q21 16p13

Age 62(50-70) 32(20-60)

Hyperuricemia/gout + +

MCKD: Clinical Features

• +/- Hypertension

• Proteinura < 1g/24 hrs

• Sodium wasting

• Mild glucosuria

Nephronopthisis

• 3 main types

– Juvenile NPH1 (Age 13 (11-17))

– Infantile NPH2 (Age 1-3)

– Adolescent NPH3 (Age 19 (16-25))

• Inheritance: Autosomal recessive

• Extrarenal in syndromes

– cerebellum, liver, bones, eye

NPHLocus Eye Cerebellum

NPH1 2q - -

NPH2 9q - -NPH3 3q - -

Cogan 2q Oculomotor - Apraxia

Senior Loken ? RP -

Joubert ? Coloboma Cerebellar vermis aplasia

Mainzer- Saldino ? [ hepatic fibrosis, cone-shaped epiphyses]

NPH1 Gene Product: NephrocystinTheory: involved in focal adhesion and or adherens

junction signaling of renal epithelial cell

Documents

Genetic Kidney Diseases October 2001. Part I Genetics Resources Specific Diseases –Nail Patella Syndrome –Cystic disorders Medullary Cystic Kidney Disease