Medical genetics III Duplications, marker chromozomes, other CHAs Duplications (dup) Origin: a)NAHR b)abnormal segregation (carriers of inversion or translocation) c)Errors in replication Inter- a intrachromozomal duplication Tandem and reverse tandem duplication Size: hunderds pb till Mbs Unequal crossing-over, duplication and muation of Bar gene in Drosophila Bar duplication in Drosophila B+,B affects facet number in compound eyes •there are about 80 microduplication syndromes •Microduplications - milder influence on phenotype, variable expressivity, can often be inherited from healthy parents Duplications – effect of gene dosage! jaws1 •increased gene expression •disorders of gene regulation and function •emergence of fusion genes •gene disruption (breaks) • Charcot-Marie-Tooth (CMT1A) – duplication of cca 1,5 Mb charcot1 Charcot-Marie-Tooth •AD neurological disorder •incidence: 1 : 2500 •gene dose effect - duplication of the myelin protein gene symptoms: muscle atrophy Clinical features •Weakness in your legs, ankles and feet •Loss of muscle bulk in your legs and feet •High foot arches, curled toes (hammertoes) •Decreased sensation or a loss of feeling in your legs and feet • 90% arise in male meiosis (recombination between repetitive sequences) Microduplication syndrome 22q11 Comparison of clinical features in deletion/duplication 22q11.2 - milder involvement, incomplete penetrance, high variable expressivity n Syndrome inv dup(15) – ofen as marker chromosome !!! dup15 Small supernumerary marker chromosomes (sSMC) nit is a small redundant chromosome that cannot be analyzed by cytogenetic banding method Characterization of sSMCs nchromosome - carries functional kinetochores, mostly regular inheritance nsmall - size usually smaller than G chromosomes; nredundant - exceptions are markers derived from gonosomes; nabsence of banding pattern - cannot be analysed by conventional cytogenetic methods !!! nmarkers sometimes do not contain centromeric DNA sequences - yet they are stable - neocentromeres noften without telomeres - circular chromosomes n Classification of sSMCs n1) Satellite marker chromosomes (up to 80%) nDistamycin A/DAPI positive - most often from chromosome 15 idic(15) - "inverted duplication 15 syndrome" nDistamycin A/DAPI - negative - frequent 13, 14, 21, 22 n idic(22) - "cat eye syndrome„ n n2) Non-satellite marker chromosomes (often ring-ring chromosomes) nDistamycin A/DAPI - positive – frequent chr. 1, 9, 16 nDistamycin A/DAPI - negative chr. 5, 8, 9, 12, 18 n n3) Marker chromosomes derived from gonosomes n frequent r(X) n n Origin of sSMCs n Origin of sSMCs n Techniques used for identification of marker chromosomes nMarker chromosomes: nwithout euchromatin - may not affect the phenotype nwith euchromatin - partial trisomy !!! nbanding (C-, Ag-NOR banding) nFISH (CEP, WCP) nSKY, M-FISH, M-BAND nMikrodisection – reverse FISH n n array-CGH (the most effective) n Finding of a marker chromosome in the fetal karyotype is always a serious problem for prognosis estimation and further genetic counselling !!!It is necessary to determine the origin !!! sSMCs and genetic counselling sSMC - case report PATIENT 1 - reason for cytogenetic examination and its result nboy (born 1984) - indicated due to mild psychomotor retardation and short stature; n nkaryotype determined 47,XY,+mar; nmarker origin: de novo, contains centromere and satellites; FOT26-1 FOT26-2 FOT26-3 PATIENT 1 - FISH investigation ncentromeric probe and whole chromosome probe 15 both negative; ncentromeric probe: 14/22 positive; nwhole-chromosome probe: 22 negative; nwhole-chromosome probe: 14 positive; n nWe've determined the origin, but we don't know what genes the marker contains... FOT26-4 FOT26-5 FOT26-6 sSMC PACIENT 2 •Child from first pregnancy •findings: hearing loss in the P ear, complete deafness in the L ear •born 2001 •both parents and younger sister healthy Karyotype: 47, XX, + mar [18] / 46, XX [12] Origin of sSMC unknown Taborska SKY: 47, XX, + mar(11) Taborska Identification of sSMCs nowadays array CGH + karyotype •on the array-CGH profile, the marker chromosome appears as a gain of genetic material •it is necessary to know the karyotype - differentiation of the marker from tandem duplication •Determination of which genes the marker contains • Profile of array-CGH with sSMC orginated from 11q12 area (5,96 Mb) Inversions (i) Origin: breaks on chromsosme 2 possible types Structural Change Structure Chromosomes Inversions Paracentric Stock Illustration 1729098124 | Shutterstock Genetic significance of inversions nInversions does not cause an abnormal phenotype in its carriers....but creates problems in heterozygotes.... n an inversion loop is created in meiosis! n nreduction of crossing-over frequency - reduction of contact sites within the loop - blockage of crossing-over - evolutionary significance of inversions (genes do not separate by c.o. and are transmitted together...) n nIn humans - clinical significance for offspring - carrier of any inversion has increased risk of abnormal gametes arising after c.o. - unbalanced CHA in offspring (dicentric chromosomes, acentric chromosomes, duplications, deletions)....abortions, affected children.... STERILITY ! Inversion and consequence of crossing-over in inverted heterozygotes unbalanced chromosome aberrations in gametes after crossing-over - duplication - deletion (peric.) or dicentric - acentric fragment (parac.) - gametes unviable ! C.O. Inversions – case report nDisruption of chr. 6 www.frontiersin.org Chromoanagenesis Event Underlies a de novo Pericentric and Multiple Paracentric Inversions in a Single Chromosome Causing Coffin–Siris Syndrome“ . Grochowski et, Front. genetics www.frontiersin.org Translocations nexchange of chromosome segments between two or more chromosomes n nreciprocal x simple nRobertsonian translocations - acrocentric chromosomes ncomplex translocations (affecting three or more chromosomes) Types of chromosomal translocations n Congentital reciprocal translocations in humans noccurrence in the population with a frequency of about 1 : 500 ndo not clearly affect the carrier phenotype (5 times higher incidence in the mentally retarded population) nsignificant cause of sterility in carriers ndue to aberrant meiotic segregation nformation of gametes with unbalanced rearrangements (duplication, deletion) nacquired translocations - positional effect in tumors - activation of oncogenes, deregulation of gene expression ! nfusion genes (e.g. Ph chromosome) n 69-99F Translocation – two color FISH Segregation in translocation heterozygotes - possible formation of gametes with unbalanced assemblies - with duplication, deletion... Segregation of adjacent chromosomes type I (homologous centromeres diverge into different daughter cells) Segregation of adjacent chromosomes type II (homologous centromeres diverge into the same daughter cell) Alternate segregation (gametes with a normal chromosome set or with two chromosomes with a reciprocal translocation) Reciprocal translocations - problems in meiosis - formation of cross structures at synapsis Gametes with unbalanced changes – dels, dups I. II. 3 possible segregation patterns Alternate segregation Unbalanced gametes normal balanced Robertsonian translocations are connected with acrocentric chromosomes in human acrocentrics robertsonian 45,XX,der(13;21)(q10;q10) or 45,XX,rob(13;21)(q10;q10) –ISCN description 45 chromozomes in karyotype ! 2 akrocentric 1 metacentric loss of short arms t13_14 der(13;14) – the most common Robertsonian translocation in humans 1 / 1300 individuals Robertsonina translocations and Down syndrome nabout 4% of Down syndrome cases - a consequence of Robertsonian translocations affecting chromosome 21 nthe parent carrier der(14;21) is normal ! but the child inherits chromosome 14 with 21! nthe theoretical risk of the child being affected by D.S. is 33% ! npopulation studies - 10 to 15% in carrier mothers Karyotype of male with Down syndome casused by translocation t(14;21) https://slidetodoc.com/presentation_image_h/366d746f8c7c9e10c87cc3733ac79162/image-36.jpg Normal 14;21 3 viable zygotes = 33% chance 45,XX,der(21;21) n100% cases of Down syndrome in offsprings