Non‐pathological paternal isodisomy of chromosome 2 detected from a genome‐wide SNP scan

Uniparental disomy (UPD) occurs when both homologs of achromosomal pair come from the father (paternal UPD) or themother(maternalUPD). Dependingonthemechanismbywhichitarises [Engel, 2006; Robinson, 2000], it can lead to heterodisomy(where both homologous chromosomes from the same parent arepresent), isodisomy (where two copies of the same homologouschromosomefromthesameparentarepresent),oramixofthetwo.UPD has been detected much more frequently for certain chro-mosomes(6,7,14,15,16)thanforothers(1,2,3,4,5,8,9,10,11,12,13,20,21,22,X),andithasyettobeobservedforchromosomes18or19[Engel,2006;Kotzot andUtermann,2005]. Whiletheremaybe real differences in the frequencies of UPD across the chromo-somes,muchofthefrequencydifferencesreportedintheliteratureprobably reﬂect differential ascertainment: UPD in certain chro-mosomes causes syndromes that are easily diagnosed.Paternalisodisomyofchromosome2iscomparativelyrareintheliterature[KotzotandUtermann,2005],andallpreviouscasesofithave been found via genetic analyses of patients with diseases orphenotypes that suggested genetic abnormalities. Thompson et al.[2002]identiﬁeduniparentalisodisomyina34-year-oldotherwisehealthypatientwithretinitispigmentosawhowashomozygousfortheMERTKmutationat2q14.1. ThispatientwassuspectedofUPDbecause the father was heterozygous for the mutation but themother was not a carrier [Thompson et al., 2002]. Similarly,Kantarci et al. [2008], Petit et al. [2005], and Chavez et al.[2000] discovered paternal isodisomy of chromosome 2 infollow-ups of cases of abnormal inheritance of Donnai–Barrowsyndrome, Crigler–Najjar type I syndrome, and steroid 5-alpha-reductase 2 deﬁciency, respectively.In the current report, we describe the ﬁrst case of full paternalisodisomy of chromosome 2 from a population-based sample forwhich no clinical phenotype was apparent. The focal individual(Twin 1) was a dizygotic twin male. Phenotypic and genomic datafor Twin 1, his co-twin sister, and both parents were collected as apart of a genome-wide association study (n¼461 twins plussiblingsand215parents)ontheBrisbaneAdolescentTwinSample(for details, see Wright and Martin, 2004). Genomic DNA wasextracted from whole blood and genotyped on the AffymetrixHumanMapping50KArrayXbaGeneChip.Informedconsentwascollected from participants and their parents, and all proceduresand protocols were reviewed and approved by the QIMR HumanResearch Ethics Committee.Both parents of Twin 1 self-reported their ethnicity as Samoan,which was supported by principal components analysis of theidentity-by-state matrix from 50K autosomal SNPs. Despite re-peatedattempts,themotherofTwin1couldnotbecontacted,andso information on pregnancy, birth, and childhood are not avail-able. Twin 1 was 22 years of age at the time of a follow-upexaminationbyaclinicalgeneticist.Otherthana2/3toesyndactylyon one foot, Twin 1 was of normal appearance and had no otherapparent physical abnormalities. His head circumference was60.5cm, and his height of 171cm was normal for his family. Hisfull-scaleIQassessedpreviouslyatage16bytheMulti-dimensionalAptitudeBatterywas95(verbalIQ¼96andperformanceIQ¼94),comparable to the IQ of his co-twin sister (88) but lower than thesample average of 112. He reported needing tutoring in juniorschool, but he successfully completed high school. He has basic