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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? • • • • • • • 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. copyright©1999 Children’s Health Care System Three kinds of genetic tests • Cytogenetic • DNA • Metabolic copyright©1999 Children’s Health Care System Karyotype 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 Genetic Testing is Context Specific • Why are you testing THIS patient at THIS time? copyright©1999 Children’s Health Care System Uses of Genetic Testing • • • • • Diagnostic Predictive Carrier Prenatal Newborn Screening copyright©1999 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? • • • • • • • 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. copyright©1999 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: • • • • • • • • 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. copyright©1999 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? • • • • • • • 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