Medical genetics I Chromosomal aberrations lAUTOSOMAL l a) Structural §Polymorphysms –different length of chromosomes in homologous pair –no phenotype effect l §Inversions –pericenric – including centromere –paracentric – does not include centromere –usually has no phenotype effect l §Ring chromosomes –breaks on both chromatids and their connection –mental and physical retardation –always newly created –sometimes redundant Chromosomal aberrations §Deletion •terminal – one break •intersticial – two breaks •deletion syndromes: •Wolf-hirschhorn syndrome; 4p deletion •Cri-Du-Chat syndrome; 5p deletion §Microdeletion syndromes: •Prader-Willi syndrome; 15q11-12 deletion •DiGeorge syndrome; 22q13 deletion •Angelman syndrome; 15q11-13 deletion •Williams-Beuren syndrome; 7q11.23 deletion – §Insertion •inserted part can be in the same or inverted position Chromosomal aberrations lTranslocation –reciprocal lmutual exchange between two or more nonhomologic chromosomes lbalanced - no phenotype effect lgenetic risics of unbalanced genom gamets formation l –robertsonian lbetween two acrocentric chromosomes lbreaks in the area of centromeres and deletion of short arms lcentric fusion of the remaining arms lbalanced – normal phenotype l –tandem ldeletion of part of an acrocentric chromosome lfusion of the remaining part with another chromosome translocation%20-%20reciprocal http://www.larasig.com/node/3628 robertsonian-translocation-13045_3 http://drugline.org/medic/term/robertsonian-translocation/ lb) Numerical lTrisomy –21 chromosome trisomy – Down syndrome –18 chromosome trisomy – Edwards syndrome –13 chromosome trisomy – Patau syndrome l lTriploidy –69,XXX; 69,XXY –nonviable –mosaic triploidy – mental retardation, syndactyly, abnormal genitals, lateral asymetry l l Chromosomal aberrations l2. GONOSOMIC lChromosome Y –structural aberrations – very rare –numerical aberrations l47,XYY – supermale syndrom lChromosome X (male) –Numerical aberration l47,XXY – Klinefelter syndrom lChromosome X (female) –numerical aberrations l45,X – Turner syndrom l47,XXX – XXX syndrom lFragile X – fraX –the most common cause of mental retardation –nonspecific phenotype – – l – Chromosomal aberrations Numerical chromosomal changes - aneuploidy https://qph.cf2.quoracdn.net/main-qimg-93c927e85dd0ef52586e3b5b1ad513ab-lq Aneuploidy - origin A)Chromosome loss l(no centromere or non-functioning l kinetochore) l lB) Robertsonian l translocations A) l lC) Errors during segregation during meiosis or l mitosis (Non-disjunction) l triz005 Anaphase Aneuploidy: non-disjunction during meiotic division I or II (gametes n+1 disomic, n-1 nulisomic) n + 1 n - 1 n + 1 n - 1 M I M II First meiotic division second division (gametes) haploid gamete Nondisjunction First Division Trisomic Trisomic Monosomic Monosomic Zygote first division second division (gametes) haploid gamete Nondisjunction Second Division Trisomic Monosomic Zygote Normal Non-disjunction can take place not only in meiosis but also in mitosis - somatic clones (cancer) Chromosomal disorders - ppt download https://slideplayer.com/slide/12220263/ Trisomy - reduced vitality and fertility - trivalent formation during gamete meiosis - haploid (n) and disomic (n+1) Trizom. cell: 2n + 1 2 Types of gametes: n a n+1 Irregular spacing of chromosomes in meiosis - sterility ! Pairing of 3 homologous chromosomes Origin of aneuploidy in humans untitled 1 Aneuploidy – trisomy, monozomy lethal (aborts), effect of gene dosage !!! lThe most common and clinically significant type of congenital aberrations ! l10% of pregnancies = chromosomally abnormal (consequence:NDD, abortions) lAny chromosome can be affected by aneuploidy... selection ! lAneuploidy - trisomy, monosomy lethal (abortion), gene dose effect ! l l lDown syndrome +21 lEdwards syndrome +18 lPata's syndrome +13 lKlinefelter's syndrome XXY lTurner syndrome X - monosomy l VSE Characteristic features of trisomies in humans a)the supernumerary chromosome is of maternal origin (90%) b) b)the cause is most often an error in division during meiosis I c) c)the frequency of trisomies in the fetus increases with maternal age Aneuploidies in humans – trisomies Viable aberrations Low gene count!! Down syndrome (47,XX or XY,+21) lIncidence 1:800 lDescribed 1866 J.L.Down lIQ 25-50 lsmall dumpy figur lround face lshort neck lmongoloid eyes lepicanthic fold lwide nose root and flattened nose lsmall mouth, large tongue, small teeth lsingle transverze palmar crease lheart diseases Causes of Down syndrome lA) simple trisomy l47,XX or XY,+21) - de novo l90% of maternal origin - in meiosis I l lB) translocation form lRobertsonian translocation der(14;21) - hereditary form of D.S. l lC) partial trisomy lmultiplied minimal critical region for DS 21q21 l lD) mosaic 47,XX,+21/46,XX l l Down's%20syndromeI Down syndrome Down_Brushfield_spots Down_simian_crease Epicanthus palmar crease lExamples of chromosomal aberrations responsible of Down syndrome Down Syndrome (Trisomy 21) - Pediatrics - MSD Manual Professional Edition http://article.sapub.org/image/10.5923.j.cmd.20150501.02_001.gif FISH micrograph of chromosomes in Down's Syndrome lt(14;21) Incidence of Down syndrome is influenced by age of mother Cause of D.S. - in 95% nondisjunction in the course of meiosis I in the mother, i.e. two copies of chromosome 21 in the egg ! Prevention/Early Detection - Down Syndrome http://downsyndrome2014.weebly.com/uploads/2/6/2/0/26201118/5926215_orig.jpg Causes of nondisjunction in oocytes and maternal age - hypotheses •Meiosis in women takes a long time - starts in the prenatal period in the fetal ovaries - lasts 10 - 50 years • •oocytes remain in M I prophase until sexual maturity - primary oocyte (about 400 at birth) •meiosis II completed at fertilization • •Nondisjunction: multiple mechanisms !!! • •CROSSING-OVER DISORDERS •COHESIN DEGRADATION DEPENDING ON MATERNAL AGE •DISORDERS OF THE DIVISION SPINDLE CONNECTION ? Edwards syndrome (47,XX or XY,+18) 1/6000, John Edwards 1960 peri215 +18 kar l Chromosomal aberrations - Knowledge @ AMBOSS Patau syndrome (47,XX or XY,+13) Claus Patau, 1960 +13 kar lhttps://pbs.twimg.com/media/EXSZhKiWsAIVZbg.jpg:large Pediatric on Squares on Twitter: "Summary of Trisomy 13 (Patau syndrome) #Pediatric #Trisomy13 #Patau https://t.co/Mwqwv3piBD" / Twitter Hexadactyly in newborn with trisomy 13 Patau - hexadact Patau syndrome – cyclopia Patau_cyclopia Patau_cyclopia_fetus Supermale syndrome (47,XYY) lincreased growth velocity lno unusual physical features lnormal testosteron level, fertility and sexual development lpossible learning disabilities ldelayed development of speech and language skills lbehavioral and emotional difficulties XYY.jpg xyy1 80´s – „double Y“ (Alien 3 – 1992) l Klinefelter syndrome (47,XXY) lVariations 48,XXYY; 48,XXXY; ltall figure lless facial and body hair lfemale distribution of body fat lhypogonadism (decreased testicular hormon function) linfertility lgynecomastia (increased breast tissue) llower intelect degree 3 klein Turner syndrome (45,X) llower birth length and weight llow hairline lpterigya lbroad chest, widely spaced nipples lsmall growth linfertility, absence of menstrual period lcoarctation of the aorta lwebbed neck llymphederma l l turner Turner File:Puffy feet.JPG XXX syndrome (47,XXX) lmajority of triple X females are never diagnosed lnormal fertility linactivated Barr body lmost often only mild effects –tall stature –small head –speech, language and learning disabilities –weak muscle tone https://www.google.cz/search?q=xxx+syndrome&source=lnms&tbm=isch&sa=X&ei=xMiIUvlHgrG0BpOYgLgL&ved=0 CAcQ_AUoAQ&biw=1440&bih=783#facrc=_&imgdii=_&imgrc=Hz1JqrGzTyKpBM%3A%3BfZOiqHDJFB267M%3Bhttp%253A%2 52F%252Fworms.zoology.wisc.edu%252Fzooweb%252FPhelps%252FZWK01047k.jpg%3Bhttp%253A%252F%252Fwww.zap pa.com%252Fmessageboard%252Fviewtopic.php%253Ff%253D5%2526t%253D7057%3B768%3B576 Triple%2BX%2BSyndrome ZWK01047k http://pics2.this-pic.com/image/triple%20x%20syndrome