J Med Genet 2001;38:497–507 497 Review article J Med Genet: first published as 10.1136/jmg.38.8.497 on 1 August 2001. Downloaded from Complex and segmental uniparental disomy (UPD): review and lessons from rare chromosomal complements Dieter Kotzot Abstract explain undiagnosed non-Mendelian dis- Objective—To review all cases with seg- orders, to recognise hotspots for meiotic mental and/or complex uniparental dis- and mitotic recombinations, and to show omy (UPD), to study aetiology and that chromosomal segregation is more mechanisms of formation, and to draw complex than previously thought. It may conclusions. also be helpful to map autosomal reces- Design—Searching published reports in sively inherited genes, genes/regions of Medline. genomic imprinting, and dysmorphic Results—The survey found at least nine phenotypes. Last but not least it would cases with segmental UPD and a normal improve genetic counselling. karyotype, 22 cases with UPD of a whole (J Med Genet 2001;38:497–507) chromosome and a simple or a non- homologous Robertsonian translocation, Keywords: genomic imprinting; isochromosome; Rob- eight cases with UPD and two isochromo- ertsonian translocation; uniparental disomy (UPD) somes, one of the short arm and one of the long arm of a non-acrocentric chromo- some, 39 cases with UPD and an isochro- Uniparental disomy (UPD) describes the mosome of the long arm of two homologous inheritance of both homologues of a pair of acrocentric chromosomes, one case of chromosomes from only one parent.1 Either UPD and an isochromosome 8 associated the presence of both homologues (“heterodis- http://jmg.bmj.com/ with a homozygous del(8)(p23.3pter), and omy”), or of two copies of one homologue 21 cases with UPD of a whole or parts of a (“isodisomy”), or a mixture of both are chromosome associated with a complex possible, reflecting the number and localisation karyotype. Segmental UPD is formed by of meiotic recombinations. Mechanisms of for- somatic recombination (isodisomy) or by mation are trisomy rescue, gamete comple- trisomy rescue. In the latter mechanism, a mentation, mitotic duplication, and postfertili- meiosis I error is associated with meiotic sation error.2 Problems associated with UPD on September 24, 2021 by guest. Protected copyright. recombination and an additional somatic are (1) placental or even fetal mosaicism mostly exchange between two non-uniparental because of formation by trisomy rescue, (2) chromatids. Subsequently, the chromatid homozygosity of autosomal recessively inher- that originated from the disomic gamete is ited mutations, and (3) aberrant genomic lost (iso- and heterodisomy). In cases of imprinting describing parent of origin depend- UPD associated with one isochromosome ent gene expression. Well known examples are of the short arm and one isochromosome maternal UPD(15) in approximately 25-30% of the long arm of a non-acrocentric chro- of patients with Prader-Willi syndrome (PWS, mosome and in cases of UPD associated MIM 176270) and paternal UPD(15) in with a true isochromosome of an acrocen- approximately 2-3% of cases with Angelman tric chromosome, mitotic complementa- 3 tion is assumed. This term describes the syndrome (AS, MIM 105830). Apart from formation by misdivision at the centro- PWS and AS, more than 100 cases of UPD of mere during an early mitosis of a mono- other chromosomes have been reviewed re- 4 somic zygote. In cases of UPD associated cently. All these cases describe UPD of a Institut für with an additional marker chromosome, whole chromosome. In contrast, apart from Humangenetik, either mitotic formation of the marker paternal UPD(11)(p15→pter) in 10-20% of Technische Universität chromosome in a trisomic zygote or fertili- cases with Beckwith-Wiedemann syndrome München, 5 Trogerstrasse 32, sation of a gamete with a marker chromo- (BWS, MIM 130650), UPD of segments of D-81675 München, some formed in meiosis by a disomic chromosomes or UPD associated with a Germany gamete or by a normal gamete and subse- complex chromosomal rearrangement have quent duplication are possible. rarely been reported. Correspondence to: Dr Kotzot, Conclusions—Research in the field of seg- Previous published reports of segmental and [email protected] mental and/or complex UPD may help to complex UPD using molecular investigations www.jmedgenet.com 498 Kotzot J Med Genet: first published as 10.1136/jmg.38.8.497 on 1 August 2001. Downloaded from i(q) i(p) i(q) i(p) AB CDE FGH Figure 1 Diagrams of segmental and complex UPD: (A) telomeric segmental UPD, (B) interstitial segmental UPD, (C) UPD associated with a “simple” translocation, (D) UPD associated with a translocation of non-homologous acrocentric chromosomes, (E) pat/mat UPD associated with two isochromosomes, one of the short arm and one of the long arm of a non-acrocentric chromosome, (F) UPD associated with two isochromosomes of the same parental non-acrocentric chromosome, (G) UPD associated with a translocation between two homologous acrocentric chromosomes, and (H) “sensu strictu” complex UPD in the instance of an additional marker chromosome. Table 1 Segmental uniparental disomy associated with a cytogenetically normal karyotype complex interaction between two imprinting centres regulating up- and downexpression of Maternal UPD Paternal UPD the paternally expressed IGF2 gene as well as KIP2 Karyotype UPD (segment) HI Ó HI Ó? Reference the maternally expressed H19, p57 , and KVLQT1 genes, all located within 11p15.5 46,XX 2p16 1 1 7 46,X? (4p) 1 × I8 (and other still unknown genes), is considered 6 46,XY (4)(q21q35) 1 1 9 to be aetiologically relevant. 46,XX (6)(p21.3) 1 1 10 Pure segmental UPD of other chromosomes 46,XY (6)(q24qter) 1 1 11 46,XX (7)(q32qter) 1 1 12 not associated with a cytogenetically abnormal 46,X? mos(11)(p15pter) * 5 karyotype is extremely rare. To the best of my 46,XX (14)(q23q24.2) 1 1 13 knowledge, only nine cases have been reported 46,X? (14)(q12q24.3) 1 1 14 46,XX (X)(q27qter) 1 1 15 so far. The first is a 22 year old healthy woman Ó 246 221 with interstitial maternal isodisomy 2p16 shown http://jmg.bmj.com/ by two markers homozygous in the child and *Approximately 20% of cases with Beckwith-Wiedemann syndrome. 7 H = heterodisomy, I = isodisomy, UPD = uniparental disomy. heterozygous in the mother. The second was detected by loss of heterozygosity in one case in are reviewed here. The aetiology and mecha- a study of linkage of DIDMOAD syndrome nisms of formation are discussed and some con- (MIM 222300) to the short arm of chromosome clusions are drawn. Segmental UPD is defined 4.8 No symptoms other than those typically as UPD of a part of one chromosome (intersti- found in DIDMOAD syndrome were present. on September 24, 2021 by guest. Protected copyright. tial or telomeric) together with biparental inher- Breakpoints were not reported precisely. Two itance of the rest of this pair of chromosomes other cases with segmental UPD were found by and a normal karyotype (fig 1A, B). Complex chance. The first with maternal isodisomy UPD is subdivided into three groups: (1) UPD 4q21→q35 was ascertained in a patient with of a whole chromosome associated with a “sim- abetalipoproteinaemia resulting from a homo- ple” translocation (fig 1C) or a Robertsonian zygous intron 9 splice acceptor G(−1) to A translocation of two non-homologous acrocen- mutation.9 A minimal region of UPD was shown tric chromosomes (fig 1D); (2) UPD associated by eight informative short tandem repeat mark- with isochromosomes of the short arm and the ers spanning a region of approximately 150 cM. long arm of a non-acrocentric chromosome (fig The second case showed paternal uniparental 1E, F) or with a Robertsonian translocation isodisomy 6p ascertained by homozygosity for a between homologous acrocentric chromosomes mutation in the steroid 21-hydroxylase gene and (fig 1G); and (3) “sensu strictu” complex UPD reduction to homozygosity in eight microsatel- defined as UPD of a part or of a whole chromo- lite markers located on the short arm of some directly involved in or associated with a chromosome 6.10 Three markers located on 6q structural and/or numerical chromosomal com- were inherited biparentally. Paternal uniparental plement other than (A) and (B) (fig 1H). isodisomy 6q24→qter was found in a male new- born with neonatal diabetes, decreased sub- Review cutaneous tissue, and a patent ductus arteriosus. SEGMENTAL UPD ASSOCIATED WITH A NORMAL Craniofacial dysmorphism included a promi- KARYOTYPE (TABLE 1) nent occiput, lambdoidal ridging, a small fonta- Mosaicism for paternal UPD of the chromo- nelle, shallow orbits, a prominent nose, dysmor- somal segment 11p15→pter is found in phic ears, gingival and labial hypertrophy, approximately 10-20% of cases with BWS.5 A macroglossia, a high palate, and micrognathia.11 www.jmedgenet.com Complex and segmental uniparental disomy 499 Table 2 Uniparental disomy of a whole chromosome associated with a “simple” translocation (non-homologous Robertsonian translocations included) J Med Genet: first published as 10.1136/jmg.38.8.497 on 1 August 2001. Downloaded from Maternal UPD Paternal UPD Karyotype UPD HI ? Ó HI ? ÓReference 46,XX,t(7;16)(q11.2q22)mat 7 1 1 16 45,XX,t(13;14) 13 1 1 32 45,XN,t(13;14) 14 5 2 2 9 2 2 23–31, 33–35 45,XX,t(14;21) 14 1 1 35 47,XY,t(3;15)(p25q11.2)pat 15 1 1 17 45,XX,t(6;15)(p25.3q11.1)pat 15 1 1 18 45,XY,t(8;15)(p23.3q11)pat 15 1 1 19 45,XN,t(13;15) 15 2 2 38 45,XY,t(14;15)mat 15 2 2 36, 37 46,XY,t(10;16)(q11.2q11.1) 16 1 1 20 Ó 1422184 4 H = heterodisomy, I = isodisomy, UPD = uniparental disomy.