Genetic counselling Renata Gaillyová Clinical genetics • Dept. of medical genetics • Genetic prevention • Genetic diseases • Patients • Chromosome abnormalities • AD,AR,XR inheritance, disorders • Prenatal diagnosis • Reproductive genetics • Hereditary cancer • Environmental hazards Dept. of Medical genetics • Genetic counselling • Laboratory part • Cytogenetic lab. (pre- and postnatal) • Oncocytogenetic lab. • Molecular – cytogenetic lab. • Lab. for DNA and RNA analysis (clinical genetics and oncogenetics) Medical genetics • Preventive • Interdisciplinary • Information from genetics • Voluntary choice for patients Genetic counselling • Family history • Pedigree analysis • Examining the patient • Laboratory analysis • Other examining - neurology, psychology, hematology, CT, MRI … Genetic counselling • Exact diagnosis (if possible) • Genetic prognosis • inheritance, genetic risk for family members, treatment, prenatal analysis Genetic prevention – I. • Before pregnancy • Folic acid (cca 1mg/day, 3+3 months) • Vaccination (rubella) • Genetic counselling • Contraception, adoption • Donor (oocytes, sperm) • Pregnancy planning • Environmental hazards (drugs, radiation, chemicals…) Prevention – II. • Prenatal diagnosis • Prenatal screening • Genetic counselling • Termination of pregnancy (ČR - end of 24. week of gestation) Genetics diseases • Chromosome abnormalities – about 0,7% • Monogen diseases – about 0,36% in 1000000 in newborns, most then 90% in childhood • Multifactorial disorders – about 80% Patients on genetic departements • Dead person • Adults • Pregnant women • Fetuses • Children Patients on genetic departements • Positive family history (chromosome abnormality, congenital malformations, mental retardation, diseases…) • Pregnant women with encrease risk for the fetus • Infertility – sterility, repeated fetal loss • Donors (gamets) • Patients with tumours Chromosome abnormalities Congenital chromosome abnormalities • Autosomes • Gonosomes • Numerous • Structural • Balanced • Unbalanced Populations frequency Chromosome abnormalities in spont. abortions Maternal age and chromosome abnormalities in AMC (per 1000) Risk of Down syndrom (live births) Down syndrome • 47,XX,+21 or 47,XY,+21 • About 1/800-1000 newborns, 1/75 SA • Hypotonia, joint laxicity, soft skin, flat face, prominent intercanthal folds, slanted palpebral fissurs, specling of the irides (Brushfield´s spots), small, down set ears, small nose, protruding tongue, simian crease in the hands (about 45%), short statue, mental retardation, congenital heart disease (50%), A-V communis +21- prenatal diagnosis • Ultrasound - 10.-12. week of. gest. • Nuchal translucency more than 2,5-3 mm • Absence of nose bone • I. trimester screening – PAPP-A • 16. week – AFP, HCG, ue3 – II. trimester screening • 20. week – congenital heart disease – not all II. Trimester screening • AFP • HCG • uE3 • Risk 1 in 250 – borderline • Maternal age, week of gestation by US Edwards syndrome • 47,XX(XY),+18 • 1/5000-10 000 in newborns, 1/45 SA • gynekotropie 4:1 • SA - 95%, death before 1 year mostly • hypotrophy, atypical hands and foots, profil, prominent nose, small chin, congenital defects Edwards syndrome • 1:5000 • růstová retardace IU • microcephalie • dolichocephalie • rozštěp patra • nízko posazené uši • micromandibula • držení prstů • další závažné VVV Prenatal dg. +18 • AFP, HCG, uE3 • Risk 1/250 - borderline • Ultrasonography Patau syndrome • 47,XX(XY), +13 • 1/5000-10 000 in newborns, 1/90 SA • 95% SA • death before 1 year mostly • cleft lip and palate bilateral, congenital defects (CNS, eyes, postaxial hexadaktily…) Patauův syndrom + 13 • microcephalie • trigonocephalie • kožní defekty ve vlasaté části calvy • vrozené vady mozku (holoprosencephalie , arinencephalie) • micro-anophthalmia • oboustranný rozštěp • hexadactilie • VCC a jiné Turner syndrome • 45,X ( in about 55% ), mosaicism, structural abnormalitites of X chromosome • 1/2500 newborn girls, min. 95% SA • prenat.- hydrops foetus, hygroma coli • postanatal lymphedema on foots, pterygium coli, congenital heart defect coarctation of aorta, small stature, other congenital defects, hypogenitalismus, hypergonadotropins, sterility Turner syndrom 45,X • 1:2000 • hygroma colli • hydrops • Low weight in newborns • Lymfoedema • Pterygia • cubiti valgi • Aortal stenosis • Small statue • Sterility Klinefelter syndrome • 47,XXY • relatively frequent 1/600-1000 liveborn males • tall stature • hypogonadism, gynekomastia • sterility, infertility Others • 47,XXX • 47,XYY • 48,XXXX • 48,XXYY…. Structural aberations • 46,XX(XY),4p- (Wolf-Hirshorn syndrome) • 46,XX(XY)5p- (Cri du chat) Cri du chat 5p- • 1:50 000 • Typicaly cri in newborns • laryngomalacie • antimongoloid • epicanthi • hypotonie • hypotrofie Wolf-Hirshorn syndrome 46,XX(XY),4p- Microdeletions • Di George syndrome (del 22q11) • Prader-Willi / Angelman syndrome (del15q11-13) • Williams Beuren syndrome (del7q11.23) Syndrom Di George • Velo - Kardio- Facial syndrome • CATCH 22 • Congenital heart desease - conotruncal, craniofacial dysmorfism, thymus aplasie, imunodefitient¨cy, hypoparathyreoidismus Williams - Beuren syndrom • del 7q11.23 • Facial dysmorfie - Elfin face, congenital heart disease, aortal or pulmonal stenosis, hypokalcemie, small statue, MR, hernie,... Prader-Willi syndrom • Hypotonie, hypotrofie in small children • PMR, small statue, obesity, hyperfagie, akromikrie, hypogonadismus • mikrodeletion15q11-12 paternal Angelman syndrom • těžká PMR, epilepsie, záchvaty smíchu, těžce opožděn vývoj řeči • mikrodelece 15q11-12 mat Telomery Mendelian inheritance Monogenetic diseases AD • The sexes are involved equaly • Heterozygotes are mostly affected clinically • risk 50% for sibs and children • new mutations • penetrance, expresivity AD - diseases • Neurofibromatosis 1 and 2 • Achondoplasia • Huntington disease • Marfan syndrome • Myotonic dystrophy AR • Heterozygotes are generally unaffected clinicaly • The sexes are involved equaly • An individual manifesting a recesive disorder usually has heterozygous parents • Once a homozygote is identified, the recurence risk for other child of some parents is 25% AR - diseases • Cystic fibrosis ( carriers in Czech Republic 1/26) • Phenylketounria (1/40) • Congenital adrenal hyperplasia (1/40) • Spinal muscular atrophy Cystic fibrosis • Localized on chromosome 7q • Frequency of Cystic Fibrosis in the Czech Republic: about 1/2000 – 1/3000 • Frequency of heterozygots in the Czech Republic about 1/25-1/29 • In 2003 about 1006 mutations in CFTR gene were identified Cystic fibrosis • Localized on chromosome 7q • Frequency of Cystic Fibrosis in the Czech Republic: about 1/2000 – 1/3000 • Frequency of heterozygots in the Czech Republic about 1/25-1/29 • In 2003 about 1006 mutations in CFTR gene were identified • The most frequent mutation in Czech Rep. F508del – about 70% The reason for CFTR gene analysis • Suspition on Cystic fibrosis in a patient • Cystic fibrosis in the family • Partners of hyterozygots for Cystic fibrosis • Repeated fetal loss • Sterility • Relationship of the partners • Others XR • Females are not affected as severaly as males or are not affected • An affected male cannot transmit the train to his sons, becose the trait is on X-chromosome, and the father must necessarily transmit his Y-chromosome to a son • All of the daughters of an affected male must be carriers, because the only X-chromosome that the father can give to a daughter contains the mutation XR • Risk for daughters of a carrier - mother • 50% for carrier • Risk for sons of carrier - mother • 50% for diseas XR - diseases • Hemophilia A and B • Duchenne and Becker muscular dystrophy • Fragile X chromosome - X-linked disease Common congenital defects Congenital heart diseases • 0,5 - 1% in liveborn infantsn - population incidence • etiology not known mostly • about 3% + chromosomal syndromes (+21,+13,+18, 45,X, 18q-, 4p-, del 22q11 Di George sy) • some mendelian syndromes associated with congenital heart disease (Holt-Oram, Williams, Noonan, Ivemark... Congenital heart diseases prenatal diagnosis • For most serious congenital heart diseases • Ultrasonography in 21. week of gestation - by specialists for prenatal kardiology Congenital heart disease - genetic risks Congenital heart disease genetic risks Cleft lip and palate • Population incidence CL 1/500-1/1000 • Multifactorial mostly • With chromosomal trisomies (+13,+18) • Syndromes associated with CL/CP/CLP • (van der Woude sy, EEC sy, Pierre Robin sequence…) • Prenatal diagnosis by ultrasonography not sure Cleft lip and palate- genetic risks Neural tube defects • Multifactorial inheritance (risk for I. degree relatives about 2 - 4%) • Maternal serum AFP screening • Prenatal diagnosis by ultrasonography • Raised AFP levels in amniotic fluid • Primary prevention in pregnancies by folic acid • Risk populations - probably related to nutritional status Prenatal diagnosis Prenatal diagnosis • Non invasive - screening • Invasive - CVS, AMC, kordocentesis Prenatal screening (CR) • Ultrasound (12. - 2 0. - 33. week) • Ultrasound 20.week – cong. defect • Ultrasound 20-22. week – cong. heart defect • Blood - biochemical screening • Free beta hCG and PAPP-A -10-14. week • AFP, hCG, uE3 - 16.week Indications for prenatal diagnosis / counselling • Advanced maternal age (35) • Risk factors for neural tube defects (US) • Family history of known conditions for which diagnosis is possible (DNA) • Known chromosomal abnormality (de novo finding in previous child, structural change in parents) • Positive prenatal screening for chromosomal abnormalities Amniocentesis Genetic counselling in infertility Infertility • Is the infertility one aspect of a genetic disorder that might be transmitted? • Will correction if infertility give an increased risk of malformations in the offspring? Infertility • Patological examination of the abortus where possible, this may identify major structural malformations. • Cytogenetic study of parents, this is especialy important where a structural abnormality is present. • In general the finding of a chromosome abnormality in the abortus but not in parent is not likely to be relevant or ti affect the genetic risks. Infertility • A search for possible lethal mendelian causes (consanguinity- risk for AR diseases, X-linked dominant disorders lethal in male, myotonic dystrophy which gives heavy fetal loss in the offspring of mildly affected women) • Inherited trombophilias in women with recurrent abortions ( factor V Leiden, factor II - G20210A, hyperhomocystinaemia ? (MTHFR - C677T) Sterility in male • AZF deletions (DAZ gene) Yq • CFTR mutations and polymorphisms Genetic risk in cancer Genetic testing in the tumours • Diagnosis • Therapy • Prognosis • Minimal residual disease Genetic risks in cancer • Tumours following mendelian inheritance(most AD, about 5%) • Genetic syndromes predisposing to malignancy • Embryonal and childhood tumours • Common malignant tumours of later life Hereditary tumours • AD • Preventive, pre-symptomatic testing • Assotiated problems • Prevention • Brest cancer – BRCA 1 and BRCA 2 • Familial Adenomatous Polyposis coli • Von Hippel – Lindau syndrome • Retinoblastoma • Neurofibromatosis • Li-Fraumeni syndrome • Lynch syndrome Familial tumours following AD inheritance • Brest cancer – BRCA 1 and BRCA 2 • Familial Adenomatous Polyposis coli • Von Hippel – Lindau syndrome • Retinoblastoma (not all) • Wilms´ tumour (syndromal form) • Neurofibromatosis • Li-Fraumeni syndrome • Lynch syndrome Genetic testing in cancer • Tests are voluntary • Mostly in adults only • In children only when prevention in childhood is present and when the risk of tumours is in childhood