Cytogenetics Chromosomal Aberrations seminar from Physiology and Pathophysiology II 21. 3. 2023 M. Chalupová Chromosomes Chromosomes • karyotype – number and appearance of chromosomes in the nucleus – 22 pairs of autosomes – 1 pairs of gonosomes (XX/XY) – in women one X chromosome inactivated • Barr body Nondisjunction Chromosomal Aberrations CONGENITAL (in gonads) • STRUCTURAL ❖ with the change of genetic information • deletion • ring chromosome • duplication • isochromosome ❖ without the change of genetic information • inversion • insertion • translocation • NUMERIC (change in the number of chromosomes) – aneuploidy – abnormal number of chromosomes (trisomy, monosomy) – polyploidy – more than two haploid (n) sets (3n = triploidy, 4n = tetraploidy) ACQUIRED (in somatic cells as an effect of mutagens) Down Syndrome • karyotype 47, XX, +21 or 47 XY, +21 • 93 % simple trisomy (due to older mother) • 4 % Robertsonian translocation • 3 % mosaicism • 1:800 neonates Down Syndrome Edwards Syndrome • karyotype 47, XX, +18 or 47, XY, +18 • 1:5000 neonates • fetal growth retardation, frequent intrauterine fetal death in II.-III. trimester • microcephaly, narrow eyelid folds, small nose, micromandible, cleft lip/palate, short neck, narrow shoulders, clenched hand with overlapped fingers • heart defects, esophageal atresia, kidney malformations • bad prognosis, suckling age survive only 12 % of children Patau Syndrome • karyotype 47, XX, +13 or 47, XY, +13 • 1:10 000–20 000 neonates • frequent premature birth in II.-III. trimester • microcephaly, trigonocephaly, skin defects, brain defects, low-set ears, cleft lip/palate, abnormal genitalia, kidney abnormalities, polydactyly • more than 90% of children die within the first year of life Cri du Chat Syndrome • deletion of the part of 5. chromosome • karyotype 46, XX, 5p- or 46, XY, 5p• 1:50000–100000 • characteristic cry of affected infants, which is similar to that of a meowing kitten, due to laryngomalacia • severe growth and psychomotor retardation, hypotonia, epicanthic eye folds, heart defects DiGeorge Syndrome • deletion of 22. chromosome, del 22(q11) • thymic and parathyroid gland aplasia • severe deffect of cellular imunity • abnormalities of calcium metabolism • facial features (dysmorphy), heart deffects Prader-Willi and Angelman Syndrome • chromosome 15q11-q13 microdeletion Prader-Willi syndrome • AD inheritance, parental imprinting • mother allele is inactive, father allele has wrong expression • hypotrophy and hypotonia, later extreme obesity, hypogenitalism Angelman syndrome • father allele is inactive, mother allele has wrong expression Klinefelter Syndrome • karyotype: 47, XXY • up to puberty normal development, can be mild psychomotor retardation, late puberty, hypogenitalism, aspermia (sterility), gynecomastia, female pattern of adipous tissue • diabetes mellitus, varicose veins, osteoporosis  hormonal substitution by testosterone before puberty  fertility can´t be influenced Turner Syndrome • karyotype: 45, X0 monosomy X • short stature (150–155 cm), lymphedema (swelling), lowset ears, broad chest • reproductive sterility • rudimentary ovaries gonadal streak • heart and kidney defects • hormonal substitution by estrogens and growth hormones Prenatal Diagnostics – Methods I. Non-invasive (screening) – ultrasound – maternal serum screening (TRIPLE TEST) II. Invasive (targeted examination of high-risk women) – amniocentesis – chorionic villus sampling – cordocentesis – fetoscopy III. Special – detection of fetal cells in maternal blood – preimplantation genetic diagnosis (PDG) • screening of congenital diseases and malformations • three-phase US screening I. 12. w.g. – gestational age, congenital defects, number of fetuses, heart rate, anencephalus II. 20. w.g. – congenital defects III. 32.-34. w.g. – growth retardation, fetal position and placenta Markers of chromosomal aberrations: • fetal hypotrophy, urogenital abnormalities, defects of abdominal wall, heart defects, pleural effusion, hydrocephalus, early growth retardation Ultrasound Screening Biochemical Screening • screening of aneuploidies • necessary to know precise pregnancy duration I. trimester PAPP-A pregnancy associated plasma protein A b-hCG subunit hCG b-core hCG in urine II. trimester AFP a-1-fetoprotein hCG human chorionic gonadotropin SP1 trophoblast specific b-1 globulin uE3 unconjugated estriol Prenatal Diagnostics – Invasive Methods Amniocentesis • extraction of amniotic fluid under US control, amniocytes (from the skin, GIT, urogenital tract…) are taken – later: 16.-18. w.g. – early: 12.-14. w.g. Cordocentesis • blood sampling from umbilical cord after 20 w.g. transabdominal under US, fetal haemoglobin assessment (HbF) • karyotype, Fra-X syndrome, hemoglobinopathy, metabolic disorders, fetal infections Chorionic villus sampling • transabdominal/transcervical under US – early: 10.-12. w.g. – later: II. a III. trimestr (placentocentesis) Fetoscopy • direct aspection by fetoscope, transabdominal, general anesthesia Prenatal Diagnostics