Download Genetic Kidney Diseases

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 yearold 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©1999
Children’s Health Care System
What are the questions that pertain to
genetic testing?
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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©1999
Children’s Health Care System
Clinical vs. Research Testing
• 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.
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Children’s Health Care System
Three kinds of genetic tests
• Cytogenetic
• DNA
• Metabolic
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Children’s Health Care System
Karyotype
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Children’s Health Care System
What are the questions that pertain to
genetic testing?
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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?
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Children’s Health Care System
Genetic Testing is
Context Specific
• Why are you testing THIS patient at THIS time?
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Children’s Health Care System
Uses of Genetic Testing
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Diagnostic
Predictive
Carrier
Prenatal
Newborn Screening
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Children’s Health Care System
63 y
d. 35 y
MVA
33 y
28 y
39 y
14 y
10 y
6y
FAP
copyright©1999
Children’s Health Care System
What are the questions that pertain to
genetic testing?
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•
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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©1999
Children’s Health Care System
Resources
• Medline
• OMIM (www.ncbi.nlm.nih.gov/)
• Genetests.org
• Geneclinics.org
• Genetics consult
Genetic Counseling
Mode of Inheritance
• FAP is inherited in an autosomal dominant manner.
Risk to Family Members
Parents. Approximately 75-80% of individuals with FAP have
an affected parent.
Siblings. If neither parent meets the clinical diagnostic criteria
for FAP, the risk to the siblings of an affected individual is low.
Offspring. Affected individuals have a 50% chance of
transmitting the mutant gene to each child.
copyright©1999
Children’s Health Care System
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
copyright©1999
Children’s Health Care System
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
copyright©1999
Children’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©1999
Children’s Health Care System
Molecular Diagnosis
Two types of DNA-based tests are available clinically: protein
truncation testing (PTT) and linkage analysis.
If PTT testing is negative, linkage testing can be considered in
families with more than one affected family member.
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Children’s Health Care
System
Testing Strategy
Test Dad
80% positive
20% negative
Positive
Direct testing available
Proceed with testing family members
Testing is highly accurate
Negative
Direct testing not useful
Linkage testing may be helpful
Linkage is less accurate
copyright©1999
Children’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©1999
Children’s Health Care System
copyright©1999
Children’s Health Care
www.genetests.org
• 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
copyright©1999
Children’s Health Care System
copyright©1999
Children’s Health Care S
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©1999
Children’s Health Care System
copyright©1999
Children’s Health Care System
PRETEST COUNSELING AND INFORMED CONSENT
Addressing:
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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.
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Children’s Health Care System
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?
copyright©1999
Children’s Health Care System
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?
copyright©1999
Children’s Health Care System
For Positive Test Results
If the Test
Purpose Was..
The Interpretation Is…
And Follow-up Includes
Genetic Counseling and...
Predictive Testing
The likelihood of showing
symptoms is increased
Life planning;
Medical Management
What are the questions that pertain to
genetic testing?
•
•
•
•
•
•
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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©1999
Children’s Health Care System
What is the Family Really Asking?
• 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?
copyright©1999
Children’s Health Care System
copyright©1999
Children’s Health Care System
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
copyright©1999
Children’s Health Care System
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
Nail Patella Syndrome
EM: glomerular basement membrane thickening
with focal, irregular internal lucencies.
Brenner & Rector's The Kidney, 6th ed
Nail Patella Syndrome
Banded collagen fibrils within the rarefied segments of GBM
Brenner & 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-NPH
Distinctive 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
NPH
NPH1
Locus
2q
Eye
-
NPH2
NPH3
9q
3q
-
Cogan
2q
Senior Loken ?
Joubert
?
MainzerSaldino
?
Oculomotor
Apraxia
RP
Coloboma
Cerebellum
-
-
Cerebellar vermis
aplasia
[ hepatic fibrosis, cone-shaped epiphyses]
NPH1 Gene Product: Nephrocystin
Theory: involved in focal adhesion and or adherens
junction signaling of renal epithelial cell