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. 1 ql3.3q21.13)281b VCFS 22ql 1.2 Multiple282 283a,d vwS 1 285a lq32-41 on September 28, 2021 by guest. Protected copyright. wS1 2q35 inv(2)(q35q37.3)217a WTI llpl3 Multiple52a,b,d zws 7ql 1.23 130a inv(7)(pl2ql 1.23)31a See Appendix for explanation of locus symbols. a=de novo aberration. b=familial transmission. c=evidence of germline mosaicism. d= unbalanced familial reciprocal translocation/inversion. e= Meera-Khan, personal communication. x = visibly unbalanced translocation.

disomy, whereby AR mutations can be disorders, and one factor that will influence the reduced to homozygosity.35 The occasional frequency of chromosome rearrangements in a occurrence of an inherited balanced transloca- specific disorder is the chromosomal localisation or inversion would therefore not be unex- tion of the corresponding gene. pected in AR disorders.36 Visible deletions among liveborns are absent or extremely rare for several regions of the human genome (figure),27 probably because The effect of chromosome localisation they are incompatible with fetal survival.37 on types and frequencies of Whereas deletions are the most frequent type chromosome rearrangements of rearrangement in those disorders which Exact determination of frequencies of chromo- map to the 'deletion viable' regions (table 1, some rearrangements in mendelian disorders figure), visible deletions do not occur in live- can only be made by systematic studies of borns affected with mendelian disorders specific mendelian disorders. This has only mapping to the 'deletion non-viable' regions been done in a few disorders, retinoblastoma (table 2). The division of the genome into a (RB1) being the classical one. The results from deletion viable and non-viable part may have RB1 may not necessarily be valid for other consequences not only for the type and fre- 716 Tommerup

Table 2 Chromosome rearrangements in deletion non-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 Miscellaneous Locus specific type

BWS 1 p15.4-15.5 del(I 1)(p 1 1 p I 3)203't t(9;1 l)(p 1l.1 lpl5.5)mato' + del( 1 )(pl 1p3)205,t1 t(4;-11)(pl 5.2;pl 5.4)mat 03b multiple dup(l lp)pat103 202d t(I1 ;22)(pI 5.5;qI 2)mat204b t(l 1;16)(pI5.5;qI2)mat053b t(I 1;12)(pI5.5;q13.1)mat'03b inv(l1)(pl 1.2pI5)mat' 26b inv(l l)(p15.4q22.3)mat053b CMPD1 17q24.3-25.1 46,XX,t( 1;1 7)(q42. 1 ;q25< 95' 46,XX,inv(17)(ql2q25)96a CMPD1/ 17q24.3-25.1 46XY,t(2; 1 7)(q35;q23-24)97a SRA1 46,XY,t(7; 1 7)(q34;q25)95" 46,XY,t(l13;17)(q331;25/95 EDA Xq13.1 t(X;9)(q13.1;p24)225 228a t(X;1 2)(q 13.1 ;q24.2)227a t(X1l)(q13. ;p36.33)224a F9 Xq27 t(X; 1)(q27;q23)229a FGDY Xql3 t(X;8)(q13;p21 .2)18b IDS Xq28 t(X;5)(q27;q31)243a IPI Xpll t(X; 15)(p ll;ql 1) or (q ll ;p li)42a t(X;9)(p 1;q34)'43a t(X; I 7)(p I 1 ;p I 1.2)15a t(X;9)(p I 1 ;q33.2) 15a t(X;13)(pl 1.21;q12.3)'44a t(X; I 0)(pl ;q22)'46a t(X;4)(q2 1 ;q28)9 t(X;5)(p 1 I.2;q35.2) 147a 45,X/46,Xr(X)41'a MNK Xql3.3 t(X;2)(ql3.3;q32.2)"7a t(X;1)(ql 3.3;q21 )§' ins(X)(p 11 .4ql 3.3q2 1 .2)mat06 NDP Xpl I t(X;10)(p 1 ;p1 4)253a inv(X)(p 11 .4q22)254b NFI 17ql 1.2 t(l;l7)(p34.3;ql 1 2)92b t(17;22)(ql 1.2;ql 1.2)93b + ?r(l7)(cen-ql2), del(17)(cen-ql2)91 OCRL Xq26.1? t(X;3)(q25;q27)256' t(X;20)(q26. 1 ;ql 1 .2)257 RSTS 16pl13.3 t(2;16)(p 13.3;p 13.3?84, t(7;16)(q34;pl13.3)8~a t(I6;22)(p13.3;?) inv(l16)(p 1 3.3;qI 3)-6 inv(16)(p13.3q13)1 See Appendix for explanation of locus symbols. * Including regions with only 1-3 reports of viable deletions. t Breakpoints not at established 1pp5.4-.5 loci. + Personal observation. § J Beck, personal communication. Cited in ref 87.

observed in 23 cases (1 7%). Furthermore, 1/3 quency of rearrangements in mendelian dis- http://jmg.bmj.com/ orders, but also for selection of strategies for of aniridia cases are sporadic and, of these, 1/3 their detection. develop Wilms's tumour.48 A visible deletion of lipl3 was seen in all 18 cases with combined WT1/aniridia in three high resolution DISORDERS MAPPING TO REGIONS WHERE cytogenetic surveys,474950 supporting the fact DELETIONS ARE VIABLE that most subjects with this combination have Retinoblastoma, Wilms's tumour, and aniridia a visible deletion. All evidence supports a The early detection of cases with deletion of a single map position for aniridia at llpl3'.5 If on September 28, 2021 by guest. Protected copyright. D group (No 13) chromosome in association so, 1/3 x 1/3 (10%) of independent cases with with retinoblastoma (RB1 )38-40 led to extensive aniridia may have a visible deletion. Since both cytogenetic screening of large series of traits are easily recognised, this is in line with patients.4''4 Consequently visible deletions the large number of cases with the WAGR have been found in 2 to 4% of all patients with complex and deletions of l 11p3 that have been RB1 when examined by metaphase technique, reported.52 As expected for contiguous gene and in 4 to 8% of patients when examined by syndromes, visible deletions and more com- high resolution techniques. Reciprocal trans- plex rearrangements within 1lp13 may not locations have been detected in approximately affect both loci.50 53 54 The limited distance 1% of patients in several independent surveys between WT 1 and the candidate aniridia using both metaphase and prometaphase reso- loci (700 to 100kb)'855 explains why a few lution, corresponding to 10% of the detected persons with Wilms's tumour and aniridia rearrangements. Thus, between 5 and 10% of have deletions below the limit of microscopic all cases with RB1 have a visible chromosome resolution.5556 Balanced chromosome re- mutation. arrangements involving lip13 have not been Larger systematic cytogenetic studies have reported in association with Wilms's tumour, not been reported in association with Wilms's but one translocation with a breakpoint within tumour (WT1)/aniridia, so a direct compari- the region has been seen in association with son with the individual traits included in the Potter syndrome,57 and three reciprocal trans- Wilms's tumour/aniridia/genitourinary mal- locations have been reported in familial aniri- formation/mental retardation (WAGR) com- dia.5 0 Taken together, the data are complex cannot be made. However, in three large patible with a frequency of chromosome series of Wilms's tumour patients, altogether rearrangements in all independent cases with comprising 1335 cases,45-47 aniridia was WT1, aniridia, and WT1/aniridia in the same Mendelian cytogenetics. Chromosome rearrangements associated with mendelian disorders 717

range as observed in RB1 (2 to 10%), with arrangements were observed.75 This may be

deletions being by far the most frequent type somewhat surprising since submicroscopic de- J Med Genet: first published as 10.1136/jmg.30.9.713 on 1 September 1993. Downloaded from of mutation. letions are extremely common in DMD, and since intragenic deletions in the 2-4 Mb DMD locus might potentially reach the lower limit of Disorders associated with imprinting: microscopic resolution. Prader-Willi and Angelman syndromes Disease associated deletions involving the Repeated observations of rearrangements distal part of Xp22.3 are seen in both males involving chromosome 15 in patients with and females, in males associated with recessive Prader-Willi syndrome (PWCR) led to numer- traits and in females with dominant traits.70 ous systematic studies.61-6 As a result, 60% of Most other X chromosome deletions are pre- patients have been found to carry detectable ferentially inactivated in female carriers, either chromosome 15 rearrangements, mostly dele- without phenotypic effects or associated with tions within 15qi 1-13 (table 1). The cytogene- Turner symptoms, including gonadal dys- tic spectrum of 300 PWCR subjects with a genesis or secondary amenorrhoea/premature chromosome 15 abnormality included 182 menopause.76 However, deletion of the region interstitial deletions, 34 unbalanced reciprocal Xq27 may result in preferential activity of the translocations, 14 Robertsonian transloca- deleted X chromosome,77 and it has been sug- tions, 16 small marker chromosomes, and four gested that this might be because of deletion of duplications,61-3 plus six balanced transloca- a locus which is involved in the normal X tions and one pericentric inversion.6' The inactivation process.78 If so, visible or submic- inversion was inherited from an unaffected roscopic deletions of Xq27 should be con- father.64 Assuming that 60% of PWCR cases sidered, along with X;autosome translocations, have a cytogenetic defect, the frequency of in females affected with disorders mapping to apparently balanced rearrangements thus ap- this region. pears to be close to that of RB1 (7 * 60/ 300) = 14%. However, it should be empha- sised that balanced rearrangements were not DISORDERS MAPPING TO REGIONS WHERE reported among 358 PWCR patients studied in DELETIONS ARE NON-VIABLE larger chromosome surveys in the period 1981 In contrast to deletions, breakpoints associated to 1991.6-63 with constitutional autosome translocations Cytogenetic deletion of 15ql 1-13 is also detected in an unbiased way in large series of observed in 50 to 60% of subjects with Angel- prenatal diagnoses79 (figure), as well as in man syndrome (ANCR).65 68 Among the fewer reported X;autosome translocations,80 81 are than 100 cases with ANCR that have been distributed all over the genome. Hence, the studied so far, one apparently balanced re- presence of disease specific translocations arrangement has been reported, a maternally would not be expected to be influenced by the inherited inversion with a breakpoint within chromosomal localisation of a disorder to the 15q13,68 which was associated with a de novo same extent as deletions. One modification of http://jmg.bmj.com/ submicroscopic deletion in the affected child.69 this is that the G-C rich chromosomal reverse The frequency of visible deletions in RB1, (R) bands contain many more genes than the PWCR, and ANCR thus varies considerably A-T rich G bands.8283 Therefore, disease spe- (- 5 to 60%), whereas the frequency of appar- cific breakpoints in translocations and inver- ently balanced cytogenetic rearrangements sions should predominantly be located in R may be within the same order of magnitude bands, which is indeed the case (figure). (_ 1%). If RB 1 is the prototype of a clearly recog- on September 28, 2021 by guest. Protected copyright. nised disease localised within a chromosomal region where gross deletion is compatible with X linked disorders fetal survival, Rubinstein-Taybi syndrome On the X chromosome, the male deletion (RSTS), von Recklinghausen neurofibromato- viable regions involve Xp22.3, Xp2l, Xq21, sis (NF1), and, to some extent, campomelic and Xq25 (figure).'7 7 Owing to the excellent dysplasia (CMPD 1) exemplify disorders map- morbid anatomy of the X chromosome,29 these ping to regions where deletions do not or only deletions are associated with recognisable rarely occur. mendelian traits, either as single gene dis- orders73 or as part of contiguous gene syndromes.'77>72 In a survey of five males with Rubinstein- Taybi syndrome, von DMD and additional clinical signs suggesting Recklinghausen neurofibromatosis, and a contiguous gene disorder, visible deletions campomelic dysplasia were detected in all five cases.7' Bivariate flow A locus for RSTS has been assigned to karyotyping of 10 visible deletions within 16p 13.3 after the identification of several inde- Xp2 1 associated with contiguous gene syn- pendent chromosome rearrangements with dromes has provided a size estimate of these breakpoints within this region.8>87 Apart from deletions intthe a a 4 to 14 Mb.72 small distal deletions associated with the hae- The frequency of visible deletions in moglobin H/mental retardation syndrome,88 patients with single gene disorders mapping to viable visible deletions of l6pl3 have not been Xp21 appears to be lower than observed in described at all.278587 This, together with the many autosomal disorders. In a systematic detection of submicroscopic deletions in 25% survey of 165 males with Duchenne or Becker of RSTS subjects with normal karyotypes,87 muscular dystrophy only, no chromosome re- indicates that it is not deletions as such that do 718 Tommerup

not occur or that are not compatible with the where visible deletions have not been de-

RSTS phenotype, but rather the size of the scribed in males.051'06 In a continuing cyto- J Med Genet: first published as 10.1136/jmg.30.9.713 on 1 September 1993. Downloaded from deletions. genetic survey of more than 200 unrelated Both RB1 and WT1 are tumour suppressor males with Menkes disease, not a single case loci.89 However, it is unlikely that this feature with a visible deletion has been detected.'07 in itself is associated with the high frequency Although the proven X linked contiguous of visible deletions seen in these disorders. gene syndromes map to those regions where Neurofibromatosis type 1 (NFl) also involves cytogenetic deletions are viable, X linked con- a tumour suppressor gene that maps to tiguous gene syndromes located within most R 17q1 1.2.6 The largest deletion which has so far band regions would be expected to be more been described in a patient with NFI was numerous, considering the high gene density 380 kb in size,90 well below the limit of micro- of R bands. However, these disorders will scopic resolution. This is in line with the probably be associated with either submicro- general absence of reported constitutive dele- scopic rearrangements'08 or with 'balanced' tions of this part of chromosome 17 (figure).27 rearrangements which will lead to limited loss In the only published case with a visible dele- of material. The same argument applies to tion of the proximal part of 17q, the deleted autosomal contiguous gene syndromes map- segment was still present in most of the cells as ping to deletion non-viable regions. a small ring chromosome.9' In contrast, and by So far, few mendelian disorders have been analogy with the findings in RSTS, reciprocal associated with visible duplications.'03109 In translocations have been described in NF1 general, duplications are better tolerated than (table 2).9293 deletions,27 so a smaller part of the genome will In campomelic dysplasia (CMPD1), chro- be duplication non-viable. However, it is rea- mosome analysis has been performed in a sonable to assume that for disorders associated number of cases because of the frequent asso- with duplication of genetic material, the chro- ciation with 46,XY sex reversal (SRA1).94 mosomal localisation may also influence the Four de novo reciprocal translocations and one occurrence of visible chromosome mutations. inversion, all involving 17q24-25, provide compelling evidence for the localisation of both CMPD1 and SRA1 to this region.9997 Only a few viable deletions involving the distal The effect of the parental origin of de part of 1 7q have been reported.98'00 Thus, novo chromosome rearrangements CMPD 1 may illustrate a disorder mapping to a De novo chromosome rearrangements are pre- region where viable deletions do occur, but dominantly of paternal origin, including all X;autosome translocations examined so only rarely. Although CMPD1/SRA1 has been 110(116 suggested to be a contiguous gene syn- far.95 This skewed parental origin has drome,95 101 visible deletions have not been several implications for the detection of struc- reported in patients with CMPD 1/SRA 1. tural rearrangements in mendelian disorders. Thus, the observed pattern of chromosome http://jmg.bmj.com/ rearrangements in CMPD 1 resembles the pattern in disorders mapping to regions where DE NOVO REARRANGEMENTS OF THE X deletions do not occur at all. CHROMOSOME As most chromosome rearrangements are Disorders associated with imprinting: paternal in origin, those involving the X must occur predominantly in females, where the

Beckwith-Wiedemann syndrome on September 28, 2021 by guest. Protected copyright. Genetic imprinting of one or more loci within phenotypic effect will be influenced by the X lip15 has been implicated in the aetiology of inactivation pattern. In balanced X;autosome Beckwith-Wiedemann syndrome.'02 103 As in translocations, where the translocation X is as Prader-Willi syndrome,61104 several different a rule the active one,808' truncation of a disease types of chromosome rearrangements have gene will lead to affected status in the female been encountered in BWS, including balanced carrier. This mechanism is a main contributor rearrangements with breakpoints in the critical to the disproportionately large number of X region of lip15, exclusively of maternal ori- linked disorders where structural rearrange- gin, and duplications of the distal part of ments have been described (figure). Since af- Ip 1 5, exclusively of paternal origin (table 2). fected females with normal chromosomes are It has been suggested that the duplications less likely to be reported, the actual frequency lead to excess expression of a paternally of X;autosome translocations in affected imprinted growth promoting gene within the females is unknown. The best estimate may region, such as insulin growth factor 2 (IGF2), come from Menkes disease (MNK), where whereas the balanced translocations might af- diagnosis, including that of females, has been fect a maternally imprinted regulator within centralised to a few centres in the world. So the region.'03 Viable deletions involving the far, two of six known MNK females are trans- distal part of l 1p5 have not been described,27 location carriers (J Beck, personal communica- so it is not likely that such deletions will be tion).'07117 seen in association with BWS either. Males will only inherit an X;autosome translocation if the translocation does not lead to gonadal dysgenesis, a frequent finding in X linked disorders females with breakpoints on the X chromo- Menkes disease illustrates an X linked disorder some.76 In addition, an associated mendelian which maps to an R band region (Xql3.3) disorder in the mother will have to be suffi- Mendelian cytogenetics. Chromosome rearrangements associated with mendelian disorders 719

ciently mild to allow reproduction. As a conse- cedure to search for the parental origin of

quence, X;autosome translocations are in chromosome rearrangements. Owing to the J Med Genet: first published as 10.1136/jmg.30.9.713 on 1 September 1993. Downloaded from general rare in males.801'8 This, together with excess of de novo rearrangements of paternal the presumed male non-viability of deletions origin, demonstration of a maternal origin of involving the major part of the X chromosome de novo rearrangements in a specific disorder (figure), led to the suggestion that intrachro- will be much more significant with respect to a mosomal rearrangements, such as inversions possible involvement of genomic imprinting'22 and shifts, will be likely types of cytogenetic than demonstration of a paternal origin.95 rearrangements in males affected with most X linked disorders.'07 These rearrangements are probably very rare.1"921 Mutational aspects with relevance for positional cloning ARE BREAKPOINTS IN BALANCED DISORDERS WHERE GENOMIC IMPRINTING IS REARRANGEMENTS LOCUS SPECIFIC? INVOLVED Although the majority of reciprocal transloca- As discussed previously, deletions involving tions and inversions included in tables 1 and 2 almost the same region of 15qll-13 are fre- are balanced at the cytogenetic level, a few of quently observed in both PWCR and ANCR. these have been shown to be associated with However, the deletion is always of paternal large submicroscopic deletions. 127128 If this origin in PWCR61'3 and always of maternal were a general feature, the assumption that origin in ANCR. 122 Although the proportion of these rearrangements involve single breaks affected subjects carrying a cytogenetically within the target locus would be erroneous.93 visible deletion is the same in the two dis- However, of 23 apparently balanced re- orders, two significant aetiological factors sup- arrangements studied at the gene level,129'38 22 port a higher frequency of PWCR than had breakpoints within the candidate gene ANCR: (1) the large excess of maternal non- locus (table 3). The assumed locus specificity disjunction'23 that may predispose to subse- of breakpoints in cytogenetically balanced re- quent uniparental maternal disomy, as arrangements in mendelian disorders therefore observed in PWCR,'24 125 and (2) the presumed seems justified, even though these rearrange- higher frequency of de novo rearrangements ments may not be truly conserved at the se- (deletions) of paternal origin which will also quence level, since small deletions from a few lead to PWCR. bp to < 30 kb have been noted (table 3). In Beckwith-Wiedemann syndrome, all balanced rearrangements involving the distal part of lip 15 have been found to be inherited LOCALISATION OF BREAKPOINTS OUTSIDE THE from the mother, similar to a preponderance of SPECIFIC TARGET maternal transmission of BWS in non-cyto- Six unrelated reciprocal translocations have

genetic familial cases.'03'26 Together with the been reported in retinoblastoma patients,4' http://jmg.bmj.com/ predominantly paternal origin of de novo re- along with 14 specific reciprocal and eight arrangements, this implies that few if any de insertional translocations. The odds therefore novo balanced rearrangements will be seem to favour a rearrangement as being dis- observed in subjects affected with BWS. In ease specific. However, they also illustrate that contrast, the mother may frequently carry the the coincidental occurrence of a rearrangement balanced rearrangement as a de novo re- is not uncommon. Further studies of the arrangement of paternal origin, or may have family, linkage studies in other families, search on September 28, 2021 by guest. Protected copyright. inherited the rearrangement from her father. for similar published reports, and comparison A similar sex dependent transmission pat- with the clinical features associated with dele- tern might be possible in balanced rearrange- tions or duplications of the regions involved ments associated with ANCR69 and PWCR,6'l 64 are needed when considering the significance where the phenotypic effect of truncation or of a detected rearrangement. deletion69 will be influenced by the parental Even if a structural chromosome mutation origin of the inherited rearrangement.68 Thus, turns out to be the aetiological factor, some apparently balanced rearrangements in PWCR mutational mechanisms have been documented should be of paternal origin,6' and of maternal or suggested which may limit the utility of origin in ANCR.69 both balanced and unbalanced rearrangements It has now become an almost routine pro- for positional cloning, or at least provide

Table 3 Molecular details of assumed locus specific rearrangements. Disorder No of studied No which truncate No with sequenced/ Size of (locus symbol) rearrangements the specific locus estimated deletion deletion DMD 11 iis29132 2 71/72 bp129 5kb'132 GCPS 3 2166 MNK 2 2138251252 NFI 1 135 RB1 4 4133 134 1 < 30 kb'34 TCD 1 i136 wS1 1 i 137 Total 23 22 720 Tommerup

conflicting data as to the disease or locus be situated anywhere on the X chromosome

specificity. (for example, IP2 in Xq28). One implication of J Med Genet: first published as 10.1136/jmg.30.9.713 on 1 September 1993. Downloaded from this would be that positional cloning of a putative IPl locus defined by X chromosome Spreading of X inactivation in X;autosome breakpoints154 may be impossible. translocations Although the majority of X;autosome translocations associated with mendelian disorders Unmasking of mutations by rearrangement have involved the X linked locus, it would be induced non-random X inactivation logical to assume that the autosomal break- If the normal X chromosome contains a point would occasionally represent the target. mutated locus, non-random X inactivation of a Most of the documented cases have been X; 13 structurally abnormal X chromosome may in- translocations associated with RB1.41 139 At the cidentally lead to clinically affected status of a cytogenetic level, 13q14 harbouring the RB1 female.'56 The erroneous conclusion that the locus seemed to be intact in all cases. The disease locus is regionally defined by the suggested mechanism for the development of breakpoints of the rearrangement may be RB1 in these cases is spreading of X inactiva- avoided by careful X inactivation studies. The tion into the autosomal segment including the possibility exists that this mechanism may be RB1 locus.'39 Inactivation of a putative locus at involved in IPL. It is uncertain whether a 9q32-34 by spreading of X inactivation has similar mechanism might be involved in two also been suggested in two X;autosome trans- X;autosome translocations with different location carrying girls with incontinentia pig- breakpoints on Xp in Rett syndrome,'57 158 a menti or hypomelanosis of Ito.'" disorder in which X linkage has been suggested by almost exclusive involvement of girls, but where linkage analysis seems to have The paradox of incontinentia pigmenti (IP1 excluded the X chromosome.'59 and IP2) At least seven, possibly eight,9 X chromosome rearrangements have been detected in sporadic Localisation of breakpoints close to but outside cases of IP, with most of the breakpoints the open reading frame within Xpl 1.141-147 IP is considered an X linked The locus for Greig cephalopolysyndactyly dominant disorder, which is lethal in males, (GCPS) has been pinpointed to 7p13 by three and which only occurs in females as a result of balanced familial translocations, 6'1'62 by dele- the functional mosaicism associated with ran- tions,'63164 and by linkage studies.'65 By the dom lyonisation. The paradoxes of IP are as candidate gene approach,7 two of the three follows. (1) The locus for familial IP has been familial translocations were found to interrupt assigned to Xq28 by linkage analysis and not to a zinc finger gene GLI3 located within 7p 13.166 149 two loci associated with However, the breakpoint in the third translo- Xp 11.148 Therefore, http://jmg.bmj.com/ IP (IP1 and IP2) have been invoked. (2) It has cation occurred about 10 kb downstream of the been suggested that two, maybe three, of the 3' end of GLI3. It was speculated that as a translocation carriers'43 145 did not have IP but result a cis acting element was brought into the hypomelanosis of Ito (HI).'40150 HI has been region of GLI3, thereby deregulating its considered the 'negative' of IP because the expression. 166 abnormal hypopigmented skin areas are distributed in the same pattern. The disorder may be a clinical manifestation of mosaicism or Dynamic mosaicism associated with ring on September 28, 2021 by guest. Protected copyright. chimerism, as evidenced by the frequent asso- chromosomes ciation with chromosomal mosaicism involv- Carriers of ring chromosomes harbouring tu- ing a variety of different chromosomes. 50151 (3) mour suppressor genes may be at increased Several different X chromosome breakpoints risk of developing chromosome specific types have been detected in the chromosomal re- of tumours, for example, r(l 3) carriers may arrangements associated with IP.'52-'54 The develop RB 1, r( 11) carriers WT 1, r(22) car- distance between two distinct regions of break- riers meningioma, etc.'55 Conversely, the de- points within Xp 1, one close to the centro- velopment of a specific type of tumour in a ring mere and one more distal, is at least 2 5 Mb,'54 carrier may suggest that a tumour suppressor suggesting that if IPI exists, the locus must be locus is located somewhere on that chromosome. extremely large, or several loci within Xp 11 Apart from the primary deletion associated may be involved. (4) Of two of the transloca- with the formation of the ring, ring chromo- tions stated to be associated with HI, one maps somes are predisposed to secondary somatic to the distal region and one to the proximal rearrangements initiated by sister chromatid region in Xpll .'54 exchanges. The result may be fragmentation, Considering the similar distribution of skin gain or loss of ring material, including com- defects in IP and HI, the defect in these plete monosomy (dynamic mosaicism). A sporadic cases with IP may also involve soma- comparison between the localisation of the tic mosaicism, perhaps associated with X inac- primary breakpoints and the likely tumour tivation. One of the rearrangements involved a suppressor loci involved suggests that the r(X),'' so dynamic mosaicism associated with secondary instability may be the most import- ring chromosome instability might even be ant factor predisposing to the development of involved,'55 in which case the gene(s) respon- tumours.'55 Thus, unlike conventional consti- sible for the pigmentary abnormalities might tutional deletions which can be used for the Mendelian cytogenetics. Chromosome rearrangements associated with mendelian disorders 721

generation of disease related deletion maps, of chromosome rearrangements in an auto-

correlations between the primary ring associ- somal dominant disorder is approximately 1 %, J Med Genet: first published as 10.1136/jmg.30.9.713 on 1 September 1993. Downloaded from ated deletions and phenotypic features should corresponding to the frequency of balanced be regarded with caution. translocations and inversions observed in RB1 Dynamic mosaicism may not be limited to (and maybe in PWCR and ANCR). If, in the development of tumours, but should also addition, visible deletions within the specific be considered as a possible mechanism in chromosome region are viable, this figure will the development of other disorders in ring be considerably higher. carriers. One possible association is Russell- The data favour that cytogenetic rearrange- Silver syndrome which shares many clinical ments will be present in a small, but not features with ring chromosome 15 deficien- insignificant, fraction of subjects affected with cies.'67 many mapped and unmapped mendelian disorders. The detection of a chromosome mutation will have obvious counselling implications Conclusions in the individual family. Considering the The present review has primarily been con- impact even a single specific rearrangement cerned with those rearrangements which can may have for gene mapping and cloning, a be expected to be encountered in a majority of more systematic effort to detect these re- mendelian disorders. Thus, the fragile site at arrangements should be pursued. In terms of Xq27 associated with the most common form value for rapid molecular isolation of the locus of X linked mental retardation has not been of interest, rearrangements involving locus discussed since it is so far the only fragile site specific breaks (for example, balanced translo- known to be associated with a specific clinical cations and inversions) will in general be the entity. most valuable ones. Although the presence of Although deletions occur less frequently additional congenital anomalies, other unex- than reciprocal translocations in newborn pected diseases, spontaneous abortions, still- screening series,33 any deletion of visible size births, etc, may suggest the involvement of a will have a big chance of involving part or all of chromosome mutation in a patient or within a a gene. This may explain why viable deletions family, subjects with balanced rearrangements are the most frequent type of cytogenetic mu- may not suffer from additional disorders.'07 tation in mendelian disorders. In contrast, a Furthermore, translocations and inversions single breakpoint or a submicroscopic deletion may be both familial and de novo mutations associated with a translocation or inversion has (tables 1 and 2). Therefore, some of the most to be more precisely located in order to involve valuable mutations in terms of positional clon- a specific locus. ing may only be detected by systematic analy- The majority of visible deletions associated SiS. with mendelian disorders has been observed in If a reciprocal translocation is detected in a sporadic cases (tables 1 and A few disorder that has not been mapped previously, 2). excep- http://jmg.bmj.com/ tions have been reported, which may be the odds will favour a breakpoint within an R explained by the presence of mosaicism in a band being the specific one. In some cases this parental carrier, or a less severe phenotype may ease subsequent attempts to confirm the associated with small deletions within certain specificity of new translocations, for example, regions, such as 13q14 associated with RB1.4 by linkage mapping. Furthermore, for large In most other situations, the assumption that scale screening programmes, high resolution chromosomal deletions are reproductive lethal chromosome analysis may be too cumbersome mutations is probably true. However, familial and time consuming. Screening strategies can on September 28, 2021 by guest. Protected copyright. occurrence of deletions associated with men- be devised which in part will alleviate this. In delian disorders can be expected in two con- disorders with a known chromosomal localisa- ditions: deletions involving the male deletion tion, complete karyotyping by high resolution viable regions of the X chromosome, and fami- technique may not be needed. In disorders lial translocations, especially insertional trans- mapping to regions where deletions are un- locations.4' 54 168172 likely to be viable, normal good quality meta- Apart from insertional translocations, other phase technique may be sufficient to detect the rare types of familial and sporadic rearrange- single break rearrangements that can be ments have been identified in association with expected. In addition, the deletion map shown mendelian disorders, in part during chromo- in the figure may provide a basis for tentative somal surveys.9' 106 As mentioned previously, exclusion mapping of mainly autosomal dom- intrachromosomal rearrangements, including inant disorders, where repeated chromosome shifts, may be the expected type of chromo- analysis has failed to identify rearrangements. some mutation in males affected with the Such disorders might be expected to map majority of X linked diseases.'07 Whether this within the deletion non-viable or less viable apparent accumulation of otherwise rare types part of the genome. This was the case with two of rearrangement may reflect ascertainments of the most recently mapped disorders, which are different from those usually encoun- R5T58587 and CMPD1 95 tered in cytogenetics (prenatal diagnosis, Linkage mapping will be greatly eased by MCA/MR, spontaneous abortions, etc) is at the rapidly increasing numbers of highly poly- present unknown. morphic microsatellites which can be analysed Without valid data derived from systematic by the PCR technique. 173 In this context a cytogenetic surveys in the majority of dis- continuous registration and clinical follow up orders, the best estimate of a basic frequency of subjects with known chromosome re- 722 Tommerup 15 Rose EA, Glaser T, Jones C, et al. Complete physical map arrangements will become increasingly im- of the WAGR region oflip13 localizes a candidate Whenever a disease has been mapped Wilms' tumor gene. Cell 1990;60:405-8. portant. J Med Genet: first published as 10.1136/jmg.30.9.713 on 1 September 1993. Downloaded from 16 Call KM, Glaser T, Ito CY, et al. Isolation and characteri- to a specific chromosome region, rapid rein- zation of a zinc finger polypeptide gene at the human of carrying chromosome chromosome11 Wilms' tumor locus. Cell1990,60:509- vestigation subjects 20. rearrangements within that region for key 17 Gessler M, Poustka A, Cavenee W, et al. Homozygous clinical features may provide essential map- deletion in Wilms' tumours of a zinc-finger gene identified by chromosome jumping. Nature 1990;343:774-8. ping and clinical data. This approach was used 18 Gessler M, Simola KOJ, Bruns GAP. Cloning of break- successfully to detectchoroideraemia 174 in a points of a chromosome translocation identifies the AN2 locus. Science 1989;244:1575-8. patient with a previously reported Xq21 dele- 19 Ton CCT, Hirvonen H, Miwa H, et al. Positional cloning tion, 175 and to show reduced nerve conduc- and characterization of a paired box- and homeobox- containing gene from the aniridia region. Cell tance velocity in a patient with a large visible 1991;67:1059-74. encompassing the CMTIA locus 20 Haber DA, Buckler AJ, Glaser T, et al. An internal duplication deletion within anlIp 13 zinc finger gene contributes to on 17p.i10 the development of Wilms' tumor. Cell 1990;61:1257-69. The construction of complete YAC 21 Pelletier J, Bruening W, LiFP, et al. WT1 mutations rapid contribute to abnormal genital system development and and cosmid contigs176177 Will greatly facilitate hereditary Wilms' tumour. Nature 1991,353:431-4. future and isolation of specific dis- 22 Pelletier J, Bruening W, Kashtan CE, et al. Germline mapping mutations in the Wilms' tumor suppressor gene are ease breakpoints/genes, for example, in com- associated with abnormal urogenital development in bination with in situ hybridisation techniques. Denys-Drash syndrome. Cell 1991;67:437-47. 23 Bruening W, Bardeesy N, Silverman BL, et al. Germline The detection of rearrangements associated intronic and exonic mutations in the Wilms' tumour gene with mendelian diseases will therefore remain affecting urogenital development. Nature Genet (WT1)1992;1:144-8. an important challenge for the clinical cyto- 24 Jordan T, Hanson I, Zaletayev D, et al. The human PAX6 geneticist. Many cytogenetic laboratories may gene is mutated in two patients with aniridia. Nature the Genet 1992,1:328-32. be discouraged from systematic studies by 25 Ledbetter SA, Kuwano A, Dobyns WB, Ledbetter DH. rarity of mendelian disorders and by the Microdeletions of chromosome l7pl3 as a cause of iso- of lated lissencephaly. Am ] Hum Genet 1992;50: 182-9. expectation of a relatively low frequency 26 Dobyns WB, Elias ER, Newlin AC, Pagon RA, Ledbetter associated cytogenetic rearrangements. As has DH. Causal heterogeneity in isolated lissencephaly. 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Am Jf Hum Appendix This appendix contains references not men- Genet 1992;51(suppl):A81. tioned in the text, listed alphabetically according to locus, BWS Beckwith-Wiedemann syndrome'02103128 including references to rearrangements included in tables 1 202 Brown KW, Gardner A, Williarns JC, et al. Paternal origin of Ii pi5 duplications in the Beckwith-Wiedemann syn- and 2, and some selected key references. Locus specific drome. Cancer Genet Cytogenet 1992;58:55-70. cross references to the text are included. 203 Haas OA, Zoubek A, Grumayer ER, Gadner H. Constitutional interstitial deletion of 1 Ipi 1 and pericentric inversion of http://jmg.bmj.com/ AGS Alagille syndrome chromosome 9 in a patient with Wiedemann-Beckwith 178 Anad F, Burn J, Matthews D, et al. Alagille syndrome and syndrome and hepatoblastoma. Cancer Genet Cytogenet deletion of 20p. J Med Genet 1990;27:729-37. 1986;23:95-104. 9 Teebi AS, Krishna Murthy DS, Ismail EAR, Redha AA. 204 Pueschel SM, Padre-Mendoza T. 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Combined CMPD1/SRAl Campomelic dysplasia/sex reversal, Goltz and Aicardi syndromes in a terminal Xp deletion: 194 are they a contiguous gene syndrome? Am J Med Genet autosomal 97101 1992;43:839-43. CMT1A Charcot-Marie-Tooth neuropathy 1109 182 Ropers HH, Zuffardi 0, Bianchi E, Tiepolo L. Agenesis of CRS1 Craniosynostosis, syndromic 1 corpus callosum, ocular, and skeletal anomalies (X- 207 Motegi T, Ohuchi M, Ohtaki C, et al. A craniosynostosis in linked dominant Aicardi's syndrome) in a girl with a boy with a del(7) (p15.3p21.3): assignment by deletion balanced X/3 translocation. Hum Genet 1982;61:364-8. mapping of the critical segment for craniosynostosis to AIED Aland island eye disease'80 the mid-portion of 7p21. Hum Genet 1985;71:160-2. ANCR Angelman syndrome (happy puppet)65"-22 208 Speleman F, Craen M, Leroy J. De novo terminal deletion 183 Williams CA, Zori RT, Stone JW, et al. Maternal origin of 7p22.l1 -pter in a child without craniosynostosis. 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