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Medical Genetics in 2006 Harry Ostrer, M.D. Human Genetics Program NYU School of Medicine A Conceptual History of Medical Genetics 1900 1901 1902 1918 1931 1937 1955 1970 1970 1976 1987 1991 2001 Mendel’s Laws rediscovered Dominant inheritance of brachydactyly Inborn errors of metabolism Anticipation described Cytoplasmic inheritance of mitochondrial DNA Linkage of color blindness and hemophilia Human diploid chromosome number is 46 Amniocentesis for chromosomal disorders Tay-Sachs screening Human globin genes cloned Predictive genetic testing for Huntington disease Medical genetics became an ABMS specialty Draft sequence for the human genome What Do Medical Geneticists Do in 2006? Diagnosis and treatment of genetic disease Presymptomatic testing for genetic disease Carrier testing, especially for high risk people Genetic counseling during pregnancy 1178 board-certified medical geneticists Case Report A man with cataracts, temporal balding, wasting of his facial muscles and a myotonic grip presents along with his young adult daughter, who had similar features. What would you do for the patient? Genetic Evaluation Data gathering History, especially family history Physical examination - major and subtle findings Pattern recognition Laboratory testing – EMG, DNA A Family with Multiple Cases of Myotonic Dystrophy cataracts Temporal balding Cataracts Hoarseness Myotonia Daytime somnolence Weakness Balding Cardiac arrhythmia Physical Diagnosis of Myotonic Dystrophy Grip release test Facial features EMG Testing for Myotonic Dystrophy Myotonic Dystrophy Results from Expansion of a Trinucleotide Repeat Correlation of Phenotype and CTG Repeat Length in Myotonic Dystrophy Phenotype Clinical Signs Premutation Mild CTG Repeat Size Age of Onset (Years) Average Age of Death (Years) None 38 to ~49 Normal Normal •Cataracts •Mild myotonia 50 to ~150 20-70 60 - normal Classical •Weakness •Myotonia •Cataracts •Balding •Cardiac arrhythmia ~100 to ~10001500 10-30 48-55 Congenital •Infantile hypotonia •Respiratory deficits •Mental retardation ~1000 to >2000 Birth to 10 45 Genetic Evaluation/Counseling Issues Patient education and treatment Natural history Risk of occurrence/re-occurrence Possibilities for diagnosis and treatment of symptoms Impact on the individual and family Results of Genetic Testing in a Family with Multiple Cases of Myotonic Dystrophy Ethical Issues Protection of the individual’s right to privacy and fair treatment (Autonomy and privacy) Competing demands of family members or mothers and fetuses (Privacy, equity and justice) Justification of exposure to increased risks (Beneficence) What Do Medical Geneticists Do in 2006? Diagnosis and treatment of genetic disease Presymptomatic testing for genetic disease Carrier testing, especially for high risk people Genetic counseling during pregnancy Case Report A woman whose 63 year old father was diagnosed with breast cancer makes an appointment for genetic testing. Her family history indicates that two paternal aunts died from ovarian cancer. She is planning in vitro fertilization because her husband has a low sperm count. She comes for her appointment with her younger, unmarried sister. Family with Multiple Cases of Breast and Ovarian Cancer Br CA 63 Ov CA 50 Ov CA36 Genes Conferring High Risk for Breast and Ovarian Cancer Locus Risk range Associated syndrome BRCA1 56-87% (by age 70) Familial breast/ovarian cancer BRCA2 37-84% (by age 70) Familial breast/ovarian cancer p53 50-89% (by age 50) Li-Fraumeni syndrome PTEN 30-40% (by age 50) Cowden syndrome MSH2, MLH1 12% (lifetime) Muir-Torre syndrome STK11 high Peutz-Jeughers syndrome Presumed Effects of Heritable BRCA1 and BRCA2 Mutations DNA damage BRCA1or BRCA2- BRCA1+ or BRCA2+ BRCA1 BRCA2 BRCA1 BRCA2 P RAD51 RAD51 failed DNA repair p53+ DNA repair p53- checkpoint activation p53 cell cycle arrest p21 no checkpoint activation p53 p21 unregulated growth Event-Free Survival By Mutation Status Proportion Event-Free 1.2 Mutation + Mutation - 1 0.8 0.6 0.4 0.2 0 0 24 48 72 96 120 144 168 Months from Robson, et al. J Clin Oncol 16:1642-1649, 1998 192 216 Second Malignancies in BRCA1/2 Carriers Mutation carriers No Mutation 12 contralateral BC 5 contralateral BC 3 ovarian neoplasia 0 ovarian neoplasia 1 AML 1 endometrial carcinoma Benefit of Risk-Reducing Surgery Breast cancer Ovarian cancer No Hazards Oophrectomy oophorectomy ratio 21/99 60/142 0.47 (21.2%) (41.3%) (0.42-0.77) 8/259 58/282 0.04 (3.1%) (19.9%) (0.01-0.06) Rebbeck, New Engl J Med. 346:1616-22, 2002 Case Report A baby died from SIDS (sudden infant death syndrome). Genetic testing in the medical examiner’s office revealed that the baby was homozygous for common mutations for MCAD deficiency. Both parents were found to be heterozygous for the mutation. In a subsequent pregnancy, the fetus was found to be homozygous normal. Fatty Acid Oxidation is Required for Gluconeogenesis glucose fatty acid oxidation protein New York Newborn Screening Program More common among AfricanEndocrine disorders Americans, Latino Americans, Congenital hypothyroidism Asian Americans Congenital adrenal hyperplasia Metabolic disorders Hemoglobin disorders Galactosemia Hb S Fatty acid oxidation disorders Hb SC Organic acidemias HB S thal Amino acid acidemias Infectious disease Genetic disorders HIV Biotinidase deficiency Cystic fibrosis Deafness More common among Caucasian-Americans Criteria for Newborn Screening Measurable burden of disease High-quality screening test available Confirmation available with gold standard test Intervention available that makes a difference System in place for providing confirmation, treatment and counseling Variation in Newborn Screening Practices Among the States as of May, 2005 What Do Medical Geneticists Do in 2006? Diagnosis and treatment of genetic disease Presymptomatic testing for genetic disease Carrier testing, especially for high risk people Genetic counseling during pregnancy Genetic Risks: What Conditions to Screen for to Identify Heterozygotes? Ashkenazi Jews Tay-Sachs Canavan Cystic fibrosis Gaucher Bloom Other Caucasians Fanconi Cystic fibrosis Niemann-Pick Fragile X Familial dysautonomia Mucolipidosis IV Greeks, Italians Africans, Asians Hemoglobinopathies Thalassemias MSUD GSD1A Fragile X Tay-Sachs Disease Is Prevalent Among Ashkenazi Jews Because of Founder Mutations ACGT Progressive neurological disease G-C Exon 11 4bp ins 90% IVS12 splice site 8% Prototype for carrier testing G-A Exon 5 Gly269Ser 1% 50 40 30 Jewish Non-Jewish 20 10 92 19 91 19 90 19 89 19 87 19 85 19 84 19 83 19 82 19 80 0 19 Number of Affected Children Impact of Carrier Testing for Tay-Sachs Disease Years Kaback, Int J Technol Assess Health Care. 10:592-603, 1994 Frequency of Carriers for Autosomal Recessive Diseases Among Ashkenazi Jews Tay-Sachs Cystic Fibrosis Canavan disease Gaucher disease Bloom syndrome Fanconi anemia Niemann-Pick disease ML4 Familial dysautonomia Fragile X MSUD GSD1A 1:11 1:9 1:5 1:4 1:3 Dor Yesharim Committee for Prevention of Jewish Genetic Diseases is a Program for the Orthodox Jewish Population Confidential genetic screening program for Jewish genetic disorders Participants are tested at around the age of 18 Designed for couples contemplating marriage The couple is notified later whether there is compatible (not both carriers) An incompatible couple is strongly discouraged from marrying each other Couples are not faced with difficult reproductive decisions What Do Medical Geneticists Do in 2006? Diagnosis and treatment of genetic disease Presymptomatic testing for genetic disease Carrier testing, especially for high risk people Genetic counseling during pregnancy Case Report A young woman with insulin-dependent diabetes mellitus presents along with her fiance for genetic counseling. During the course of the interview, we discovered that the fiance had neurofibomatosis I, a condition that was diagnosed during his physical diagnosis course in medical school. In addition, it became apparent that the young woman had hypohydrotic ectodermal dysplasia, a condition that she shared with her mother and two sisters. Case report (continued) We counseled the couple that the likelihood of their having a normal fetus was 21%. w/o NF1 - 50% w/o HED - 50% w/o diabetic embryopathy - 85%. Some weeks later we learned that the couple split up. Fetal Nuchal Translucency Measurement Improves Detection Rate for Chromosomal Abnormalities GA: 11 wks, 3 days to 13 wks, 6 days Crown-rump length: 45 to 84mm Increased in chromosomal disorders, congenital heart disease congenital infection fetal hydrops rare genetic disease (Noonan syndrome, lethal multiple pterigium, AR cystic hygroma) FTS Studies Using free-Beta HCG / PAPP-A / NT Author Orlandi (1997) Biagiotti (1998) De Biasio (1999) De Graaf (1999) Spencer (1999) Krantz (2000) Niemimaa (2001) Wapner (BUN) (2002) Schucter (2002) Von Kaisenberg (2002) Bindra (2002) Spencer (2003) Sheffield (2003) Borrell (2004) CUBS (2004) Nicolaides (2005) Total N 744 232 1,467 300 1,156 5,718 1,602 8,514 4,939 3,864 15,030 10,458 18,140 2,780 5,084 75,821 155,849 FPR 5.0 5.0 3.3 5.0 5.0 5.0 5.4 5.0 5.0 6.6 5.0 5.0 5.0 3.3 5.9 5.2 5.0 Sensitivity 6 of 7 24 of 32 11 of 13 31 of 37 187 of 210 30 of 33 4 of 5 48 of 61 12 of 14 16 of 19 74 of 82 23 of 25 60 of 64 7 of 8 14 of 15 301 of 325 848 of 950 (87%) (76%) (85%) (85%) (89%) (91%) (80%) (79%) (86%) (84%) (90%) (92%) (94%) (88%) (93%) (93%) (89%) Interphase Amniotic Fluid FISH Analysis for Chromosomal Aneuplodies Protocol 2-4 ml clear amniotic fluid Centrifuged, fixed and dropped on slide Hybridized with chr 13, 18, 21, X, Y probes Count at least 50 cells >85% aneuploid abnormal >85% euploid normal Others indeterminate How Do Genes Influence Who We Are? Phenotype: Predisposition to superior athletic ability Predisposition to breast cancer Predisposition to sociopathic behavior Genetic testing "will enable every set of parents that has a little baby to get a map of the genetic structure of their child." They will be able to "plan that child's life: to organize the diet plan, the exercise plan, the medical treatment that would enable untold numbers of people to have far more full lives." President Bill Clinton, 1996 Campaign