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Mendelian Cytogenetics. Chromosome Rearrangements Associated with Mendelian Disorders

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Mendelian Cytogenetics. Chromosome Rearrangements Associated with Mendelian Disorders J Med Genet 1993; 30: 713-727 713 REVIEW ARTICLE J Med Genet: first published as 10.1136/jmg.30.9.713 on 1 September 1993. Downloaded from Mendelian cytogenetics. Chromosome rearrangements associated with mendelian disorders Niels Tommerup The first successful mapping of a mendelian stantial part of the heterogeneity and overlap disorder by chromosome rearrangements was in syndromology: contiguous gene syndromes that of the Duchenne muscular dystrophy where microscopic or submicroscopic dele- locus to Xp21.1-5 Since then, chromosome ab- tions (or duplications) involve an array of errations which delete, truncate, or otherwise closely positioned genes.'314 A purpose of the rearrange and mutate specific genes have not molecular characterisation of contiguous gene only helped in the mapping of other disease syndromes is to identify individual genes loci,6 but have turned out to be key elements responsible for specific components of the for the rapid isolation of disease genes by phenotypic complex. This is probably best positional cloning strategies.7 Accordingly, a illustrated by the molecular studies of listing of the clinical disorders in which associ- deletions and translocations involving llp13 ated chromosome rearrangements have been associated with various combinations of described forms a part of the Human Gene Wilms's tumour, aniridia, genitourinary mal- Mapping Workshops.6 Although the early suc- formations, and mental retardation (WAGR cess led to a proposal for systematic cytogene- complex).'5 The resulting isolation of candi- tic analysis of subjects with mendelian dis- date genes for Wilms's tumour (WT1)'6 7 and orders,8 this has rarely been done. A common aniridia (AN2, PAX6)'8'9 now provides a feeling is that, as mutations, these rearrange- means for molecular studies and delineation of ments are rare exceptions. The aim of the monogenic conditions within 1 lpl3.2"24 Simi- present review is to document that they may be larly, the dissection of the phenotype in rare, but are not exceptions, and to focus on MDCR has begun with the demonstration of http://jmg.bmj.com/ factors which may influence their occurrence submicroscopic deletions in cases with isolated and facilitate their detection. lissencephaly.2526 Any visible chromosome imbalance almost invariably represents a contiguous gene dis- in relation order, but few chromosomal syndromes in- Contiguous gene syndromes clude features of sufficient specificity to permit to mendelian genetics a correlation with a recognised mendelian dis- on September 28, 2021 by guest. Protected copyright. Genetic disorders are usually classified into chromosomal, and multifactorial order. This includes many of the classical mendelian, chromosome disorders,27 as well as newly categories. Mendelism involves transmission recognised ones.28 Although these chromo- of traits which traditionally are patterns some aberrations may not have immediate im- genes. The thought to be determined by single plications for known mendelian traits, future mere fact that a chromosome rearrangement molecular dissection of these disorders may to of a mendelian may lead the development this. disorder suggests that this distinction between change mendelian and chromosome disorders may be arbitrary.9 This is illustrated by Miller-Dieker syndrome (MDCR), lissencephaly with a char- Chromosome rearrangements in acteristic facial appearance, that was originally relation to autosomal dominant, listed as an autosomal recessive condition autosomal recessive, and X linked owing to the presence of familial cases with disease two or more affected sibs.9 All familial cases Specific chromosome rearrangements have analysed have so far been shown to be associ- predominantly been described in autosomal The Danish Centre for Human Genome ated with unbalanced segregation of familial dominant (AD) and in X linked conditions. Of Research, The John F translocations or inversions, leading to seg- the 625 chromosomally mapped loci associated Kennedy Institute, GI mental aneuploidy (deletion) of a distal seg- with genetic disorders, 54 (8-6%) are X Landevej 7, DK-2600 ment not of the Glostrup, Denmark, of 17p.1''2 Thus, MDCR associated linked.29 However, more than one third and Department of with a chromosome abnormality is probably approximately 70 mendelian disorders associ- Medical Genetics, best explained as an autosomal dominant con- ated with a specific chromosome rearrange- Ullevaal University dition where all mutations are de novo. ment are X linked6 (figure). This excess can be Hospital, Oslo, Norway. MDCR also illustrates a mutational explained by almost routine application of N Tommerup mechanism that may eventually explain a sub- cytogenetic analysis in two particular groups of 714 Tommerup J Med Genet: first published as 10.1136/jmg.30.9.713 on 1 September 1993. Downloaded from I|1 BWSt IBWS HPE2 )DGCR2 AN28 GRt) II II I II II .Al VI I 9 10 11 12 7 6 vws - wsij Al 2 S!S/CDPX1 /MRX2/ AIC* iSrS/KAL1I/OA1GFDH/AIC 1 AIED DMD/BMD AHC/GK/DMD/ NDP XK/CYBB/RP3 IP1 EDA MBS MBS FGDY HPE4 ~~~~~~~MNK* RBI RB1 TCD/ TC D IDFN3 ~~AG ~~ SRY gHP4 g i DGCR S ILYP AZF AZF OCRL HSCR IIDS IFRAXA ~~~~~~~~~~TKC 13 14 15 16 17 18 19 20 21 22 X y Deletion Duplication 0 Locus specific rearrangement (translocation, inversion) http://jmg.bmj.com/ *Fragile site g Regions where viable deletions have been described. g Regions with only 1-3 reports of viable deletions. on September 28, 2021 by guest. Protected copyright. Translocation breakpoints detected in a non-biased way in prenatal diagnosis79 Localisation of mendelian disorders where chromosome rearrangements have been described. For explanation of symbols, see Appendix. patients: females affected with X linked dis- chromosome mutation will only show an AR eases, suggesting X;autosome translocations, locus if the other allele happens to be mutated and males suffering from two or more X linked (unmasking of heterozygosity),32 and this will disorders, suggesting a contiguous gene syn- be a rare occurrence as the gene frequencies for drome. Since there are no a priori reasons to even the most common AR disorders do not believe that chromosome rearrangements exceed 1/25 to 1/50. Owing to the number of should be less frequent in AD than in X linked recessive traits, and the relatively high fre- disorders, the underrepresentation in AD dis- quency of familial translocations and inver- orders is probably because of ascertainment sions in man,33 some of these breakpoints may bias. affect recessive loci. Thus, several murine The cytogenetic data in autosomal recessive balanced translocations are lethal in the (AR) disorders are so scanty that reliable state- homozygous state.34 The risk of unmasking of ments regarding their frequency cannot be heterozygosity by a transmissible chromosome made. In only one AR disorder (Zellweger rearrangement will increase with the number syndrome) has more than one chromosome of individuals that receive the rearrangement. rearrangement been described, a de novo dele- In addition, familial translocations may tion and a de novo inversion.303' A specific predispose to the formation of uniparental Mendelian cytogenetics. Chromosome rearrangements associated with mendelian disorders 715 Table I Chromosome rearrangements in deletion viable regions. Disorder Chromosomal Type of rearrangement J Med Genet: first published as 10.1136/jmg.30.9.713 on 1 September 1993. Downloaded from (locus symbol) localisation Deletions (No) Locus specific type AGS 20pl 1.23-12.1 Multiple'78b 179a AHC Xp2l Multiple72 180a AIC Xp22.3 Multiple70 181a t(X;3)(p22;ql2)182. AIED Xp2l i 180a ANCR 15ql 1-12 Multiplemat)6568a8d 122a 183a inv(l5)(pl qI3)mat6'696 AN2/PAX6 lpl3 Multiple52a7d 54d t(4;I 1)(q22;p1 3)60b t( 1 ;22)(pI 3;q12.2)?8 t(5;1 1)(qI3.1;p13)26 ANKI 8plI.1 3187a 188a 186c? t(5;12l)(plt(8; 12)(piI 1;p13)'6'61 p 1 3) 184b t(3;8)(p21;pl 1)185b APC 5q22 5189a 191a 190b 183d t(5;10)(q22;?)' AZF Yqll Mult' le'93-196a BPES 3q23 4199a 172d t(3;1 1)(q21;q23)90b t(3;4)(q23;p15.2)20a t(3;8)(q23;p21.1)17 CDPX1 Xp22.3 Multiple70 CRS1 7p21 Multiple207 208a CYBB Xp2l Multiple72 209 210a,b DFN3 Xq2l Multiple37 211 DGCR1 22ql1 Multiple213-2l7a,d t(2;22)(q14.1;ql 1.1)212b DGCR2 lOpl3 7214a,d 8a DMD/BMD Xp2l Muit ile77 72a,b Multiple2""a GCPS 7p13 3163a I 4a t(3;7)(p21 .Ip13)960b t(6;7)(q27;p13) 61b t(6;7)(qI2;pl 3)162 GK Xp2l Multiple7' 72a,b HLD 4q12 t(4;5)(q2 1;p 15 *3)2 t(4;6)(q2 1;p24)2 2b HMRD 16p13.3 488a,d HPE2 2p2l 4233a HPE3 7q35 Multiple234 236 237a,d t(7;9)(q36;q34)235b HPE4 18p Multi le234 238a,d HSCR 13q33.1 3239-24Ial KALI Xp22.3 Multiple70a LGCR 8q24.11 Multiple'27 244 245 248a,d t(2;8)(q33;q24. 1)127 t(4;8)(pl5.3;q24. 1)127 t(8;1 1)(q24.1 1;p15.5)246 inv(8)(ql 1.23q21 .1 )247b LYP Xq25 173b MBS 13ql2.2 1249a t(1;13)(p34;ql 3)250b MDCR 17pl3 Multiple"o- 2 25 26a,d MRX2 Xp22.3 Multiple70 NF2 22q 12.2? t(4;22)(q12;qI OAI Xp22.3 Multiple?70 2.2)25b PBT 4ql2-13 3257 259 260a t(4;15)(ql2q21;ql 1)2511 PWCR 15ql 1-12 Multiple(pat)41851,,d 1 X;A translocation (see ref 61)8 5 autosomal translocations61b inv(15)(pl3ql 3)pat64 RB1 13q14 Multiple3844a,b,c?,d Multiple4' SHFD1 1.2-21.3 7264 2698 7ql t(5;7;9)(qI 1 .2q34;q21 .2q31 .3;q22.1)21, http://jmg.bmj.com/ t(7;9)(ql SRY Ypl2 Multiple7Oa 267 268a 1.21;p12)263b SS Xp22.3 Multiple798 STS Xp22.3 Multiple701 TCD Xq2l Multiple37 174b 271a,b t(X;7)(q2 1.2;p14)2711 t(X;1 3)(q21 .2;p1 2)274, TKC Xq28 t(X;3)(q28;q21 )275a t(X;10)(q28;ql 1.2)275, TRP1 8q24.1 1 5276-280a,c dir ins(8)(q24.
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