Clinical Genetics Congenital chromosomal aberrations Renata Gaillyová 2014 C:\Users\Jitka\Desktop\Nová složka\images6.jpg Chromosomal aberrations chromosome1 0,6-0,7% live born VZOR2karkon Karyotyp 46,XY – normal in men VZOR2mit G-pruhy Chromosomal aberrations •Inborn: •20 – 50% all conceptions •50 – 60% abortions (I. trimester) •0, 56 - 0,7 % live born • •Acquired: •Oncology – hematooncology •Risks in enviroment (drugs, cigarettes,…) Congenital chromosomal aberrations •Autosomes •Gonosomes • •Numerous •Structural • •Balanced •Unbalanced • Frequency of congenital chromosomal aberations •Live-born children 0,6% •Balanced 0,2% •Unbalanced 0,4% •SA 50% •Still born children 11,1% •newborns with congenital malformations 15% •Premature babies 2,5% Chromosomal aberrations in spont. abortions Frequency Cytogenetic analysis •Prenatal • • • • • • •Postnatal • Material for cytogenetic analysis •Cells from amnionic fluid •Chorion villi •Placenta •Fetal blood •Tissue – aborted fetuses • •Peripheral blood lymfocytes •Tissue (skin biopsie, bucal smear,…) • • Indications for postnatal cytogenetic analysis •The typical phenotype •Newborn with multiple malformations •Psychomotor / mental retardation •Stigmatization •Genital anomalies •Disorders of sex development •Infertile couples •Gametes donors Indications for amniocentesis •Positive biochemical screening •Pathological ultrasound findings in the fetus •Balanced chromosomal aberrations in parents •Chromosomal aberrations in the family •Age of parents - ??? • •Monogenic disease present in the family • Maternal age and chromosome abnormalities in AMC (per 1000) Down syndrome • • karyotyp +21 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, Brushfield´s spots of the irides, small, down set ears, small nose, protruding tongue, simian crease in the hands (about 45%), short statue, mental retardation, congenital heart disease in about 50% of patients with DS, (atrioventricular canal) +21 Down syndrome (G-banding) karyotyp +21 47,XX,+21 Happy nature Vision and hearing disorders Hypothyroidism Correlation between positive stimulation and height IQ Male sterility Alzheimer-like symptoms in 40 Výsky T 21 1 na 800. Je dobre známa závislosť výskytu trizómie 21 na veku matky , emiprické riziká stúpaju s vekom matky. U muža táto závisloslosť nebola popísaná. Risk of Down syndrome (live births) Cytogenetic findings in DS in Czech republic 1994 - 2001 Down syndrome- prenatal screening •I. trimester screening – combined screening •10.-14. week of gestation •Ultrasound •Nuchal translucency - NT ( ) •(Absence of nose bone) •Blood •PAPP-A ( ) •free-beta hCG ( ) •Fals positive results less then 5% •Reveals about 95% of fetuses with Down syndrome •1/100 – positiv – genetic counselling and karyotiping •1/100-1/1000 – US and genetic counselling •1/1000 – negativ - US Down syndrome- prenatal screening •II. trimester screening – biochemical screening •16. -18. week of gestation •AFP – alpha-fetoprotein ( ) •total hCG - chorionic gonadotropin ( ) •uE3 - unconjugated estriol ( ) • •Fals positive results about 5% • •Reveals about 70% of fetuses with Down syndrome • •1/250 – positiv •1/250-1/350 – border •1/350 - negativ Down syndrome- prenatal screening •Ultrasound •10.-14. week •NT •NB •Some congenital malformations •20. week •US •Congenital malformations •congenital heart disease trizómia 18 Magenhaimová NT UZ trizómia 18 magenheimová graf Nuchal Translucency Novo zavedený kombinovaný test v I.trimestr gravidity sa zdá sa ako najefektivnejší na vyhladávanie chromozómových aberácií. Tehotenský plasmatický protein A (PAPP A) a volná beta podjednotka hCG. Umožní individuálny odhad rizika chromozómovej aberácie. Tento skríning sa javí špecifickejší, presnejší, ako je zavedený II. Trimestrový skríning. Má ešte jednu výhodu a tou je včasnejšia diagnostika chromozómovej aberácia, pretože fetálny karyotyp sa získáva z choriových klkov spravidla v 12. týždni gravidity oproti plodovej vode, ktorú je možné odobrať až o mesiac neskor. I. Trimestr screening •Age – 28,8 •Week of gestation 13+2 (US) •FßhCG 26,66 - 1,09 MoM •PAPP-A 2,93 – 0,82 MoM •NT 2,0mm - 1,76 MoM • •Risk for Down syndrome in age 28,8 years – 1/1100 • •Combine risk for DS 1/2700 • •Negative I. trimestr screening I. Trimestr screening •Age – 33,6 •Week of gestation 12+5 (US) •FßhCG 113,4 – 3,41 MoM •PAPP-A 1,86 - 0,55 MoM •NT 1,6 mm – 1,25 MoM • •Risk for DS in age 33,6 years – 1/550 • •Combine risk for DS 1/80 • •Positive I. trimestr screening I. Trimestr screening •Age – 33,6 •Week of gestation 12+5 (US) •FßhCG 113,4 – 3,41 MoM •PAPP-A 1,86 - 0,55 MoM •NT 1,6 mm – 1,25 MoM •Risk for DS in age 33,6 years – 1/550 •Combine risk for DS 1/80 •Positive I. trimestr screening • •Recommendation •Genetic consultation •Karyotyping of the fetus •Detailed ultrasound examination of the fetus II. Trimestr screening •Age – 29,9 •Week of gestation •15+1 •AFP 48,0 - 1,66 MoM •uE3 3,09 – 1,07 MoM •Total hCG 40,2 – 0,99 MoM • •Risk for DS in age 29,9 years – 1/1000 •Combine risk for DS less then 1/50 000 •Negative II. trimester screening • •Recommendation •Detailed ultrasound examination of the tetus in 20. week of gestation II. Trimestr screening •Age – 33,7 •Week of gestation •15+3 •AFP 21,1 – 0,71 MoM •uE3 1,55 – 0,49 MoM •Total hCG 35,1 – 0,95 MoM • •Risk for DS in age 33,7 years – 1/540 •Combine risk for DS 1/220 •Positive II. trimester screening • •Recommendation •Genetic Consultation •Karyotyping •Detailed ultrasound examination of the fetus • II. Trimestr screening •Age – 25,7 •Week of gestation •20+5 •AFP 27,6 - 0,50 MoM •uE3 6,28 – 0,38 MoM •Total hCG 4,2 – 0,21 MoM •Risk for DS in age 25,7 years – 1/1300 •Combine risk for DS 1/6300 •Risk for Edwards syndrome 1/3 •Risk for Smith-Lemli-Opitz syndrome 1/65 • •Recommendation •Genetic Consultation •Fetal karyotyping, DNA of the fetus (SLOS) •Detailed ultrasound examination of the fetus •DNA analysis SLOS – both parents • • Integrated screening •Age – 25,8 •Week of gestation •1. 12+6 (US) •2. 15+6 •AFP 29,8 – 0,97 MoM •uE3 3,45 – 0,96 MoM •Total hCG 48,5 – 1,48 MOM •PAPP-A 4,1 – 1,16 MOM •NT 1,3 mm – 1,01 MoM •Risk for DS in age 25,8 years – 1/1300 •Combine risk for DS 1/15 000 •Negative integrated screening • •Recommendation •Detailed ultrasound examination of the tetus in 20. week of gestation Non-invative prenatal testing (NIPT) •examination of free fetal DNA in maternal plasma • •performed outside the Czech Republic • •reliability over 98 % • 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 •IUGR, hyopotrophie •microcephalie •dolichocephalie •Cleft palate •Down set ears •micromandibula •Hands, feets •Other cong. malformations 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 hexadactily…) Patau syndrome •Microcephalie •Trigonocephalie •skin defects in the hairy part calva •congenital defects of the brain (holoprosencephalie, arinencephalie) •micro-anophthalmia •Cleft lip, palate hexadactilie •heart defects • 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-infertility Turner syndrome 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 Klinefelter syndrome 47,XXY Klinefelter Others gonoseme abnormalities •47,XXX •47,XYY • •48,XXXX •48,XXYY Structural chromosomal aberrations •deletion or a duplication of the genetic material of any chromosome, atypical structure - side by side to get the genetic material, which there normally is not - the effect of positional •partial-partial deletions •partial trisomy •inversions, insertions, duplications ... mutation2 Wolf-Hirshorn syndrome 46,XX(XY),4p- •severe mental retardation •typical craniofacial dysmorphia - hypertelorism, pear nose, carp mouth, •pre-and postnatal growth retardation, •failure to thrive •other associated developmental defects - heart, urogenital tract ... Cri du chat syndrome 46,XX(XY),5p- •anomalies of the larynx causes the characteristic cry of a similar feline meow (only in infancy) •low birth weight and length •mental retardation, short stature, failure to thrive, small moon shaped face, the position antimongoloid eye slits, mikrocephalie •Other malformations and birth defects Cri du chat 46,XX(XY),5p- •1:50 000 •Typicaly cri in newborns •laryngomalacie •antimongoloid •epicanthi •hypotonie •hypotrofie Mikrocytogenetic Molekular cytogenetic •FISH (fluorescenc in situ hybridisation), M-FISH, SKY (spektral karyoptyping), CGH (komparativ genom hybridisation), MLPA •mikrodeletions or mikroduplications, marker chromosoms, complex rearegements, oncology – oncocytogenetics,fast prenatal diagnostics …) •fast methods (possible for prenatal dg) •metafase and intesfase examination FISH M-FISH (multicolor) Spektral karyotyping (SKY) DNA2 Comparativ genom hybridisation 8dobr1 pokus88d MLPA Multiplex Ligation-Dependent Probe Amplification mrc_holland_font40 the_mlpa_reaction1 2 3 4 5 6 7 8 9 10 11 12 Array CGH •DNA mikroarray • •Chip technology • 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 DiGeorge DIGPOZ~1 Williams - Beuren syndrome •del 7q11.23 • •Facial dysmorfie - Elfin face, congenital heart disease, aortal or pulmonal stenosis, hypokalcemie, small statue, MR, hernie,... obr2a Foto WB sy Prader-Willi syndrome •Hypotonie, hypotrofie in small children • •PMR, small statue, obesity, hyperfagie, akromikrie, hypogonadismus • •mikrodeletion15q11-12 paternal • Angelman syndrome •Severe mental retardation •Epilepsie •Laughter •severely delayed speech development •mikrodeletion 15q11-12 mat 922-99upr The telomeres Rearangement in about 6-8% children with mental retardation with or without congenital defect (FISH, HR-CGH, MLPA)