Inversion of the Williams syndrome region is a common polymorphism found more frequently in parents of children with Williams syndrome

Abstract

Williams syndrome (WS) is a multisystem disorder caused by deletion of about 1.55 Mb of DNA (including 26 genes) on chromosome 7q11.23, a region predisposed to recombination due to its genomic structure. Deletion of the Williams syndrome chromosome region (WSCR) occurs sporadically. To better define chance for familial recurrence and to investigate the prevalence of genomic rearrangements of the region, 257 children with WS and their parents were studied. We determined deletion size in probands by metaphase FISH, parent-of-origin of the deleted chromosome by molecular genetic methods, and inversion status of the WSCR in both parents by interphase FISH. The frequency of WSCR inversion in the transmitting parent group was 24.9%. In contrast, the rate of inversion in the non-transmitting parent group (a reasonable estimate of the rate in the general population) was 5.8%. There were no significant gender differences with respect to parent-of-origin for the deleted chromosome or the incidence of the inversion polymorphism. There was no difference in the rate of spontaneous abortion for mothers heterozygous for the WSCR inversion relative to mothers without the inversion. We calculate that for a parent heterozygous for a WSCR inversion, the chance to have a child with WS is about 1 in 1750, in contrast to the 1 in 9500 chance for a parent without an inversion.

An exploratory study of predisposing genetic factors for DiGeorge/velocardiofacial syndrome

“…Parental inversion polymorphisms have also been proposed as a susceptibility factor for NAHR events in multiple genomic disorders, especially in Williams-Beuren syndrome202122. With regard to the 22q11.2 inversions, in agreement with the work of Gebhardt et al 44.…”

“…CNVs in the LCRs flanking the critical regions have been described as predisposing factors for Smith-Magenis and Potocki-Lupski syndrome1415, Williams-Beuren syndrome16 and 16p12.1 microdeletion disease17. Inversions of the critical region have been related to the occurrence of Prader-Willi/Angelman syndromes1819, Williams-Beuren syndrome202122, Smith-Magenis syndrome23, 17q21.31 microdeletions24 and t(8;22)25, among other genomic disorders26. According to these observations, genomic architecture variations in parents-of-origin may confer a higher likelihood of LCR misalignment during meiosis and consequently a higher susceptibility to NAHR events.…”

Characterizing polymorphic inversions in human genomes by single-cell sequencing

“…1C, red arrowheads), including a well-documented homozygous inversion on the p-arm of Chromosome 8 (Chr 8) (Hollox et al 2008;Salm et al 2012;Alves et al 2014) and a heterozygous inversion on the q-arm of Chr 7, that are disease-linked (Fig. 1C, boxed regions; Osborne et al 2001;Tam et al 2008;Hobart et al 2010). Strand-seq sequencing reads were BED-formatted and uploaded as custom annotation tracks onto the UCSC Genome Browser (GRCh37/hg19 assembly) ( Fig.…”

“…For instance, the large inversion on Chr 8p23 exhibits a clinal distribution correlating with geographic distance from Ethiopia (Salm et al 2012) and confers a reduced risk of autoimmune diseases (Hollox et al 2008;Salm et al 2012;Alves et al 2014). The gene-rich polymorphisms found on Chr 7q11 and 15q13 correspond to inversions associated with complex neurological disorders, including mental impairments (Osborne et al 2001;Tam et al 2008;Hobart et al 2010), seizures (Koolen et al 2006;Sharp et al 2008), or schizophrenia (International Schizophrenia Consortium 2008Stankiewicz and Lupski 2010). A Chr 17q21 inversion that is common in Europeans (with a minor allele frequency of 0.2) predisposes children of heterozygous carriers to a microdeletion syndrome associated with developmental delays (Stefansson et al 2005;Koolen et al 2006;Zody et al 2008;Donnelly et al 2010).…”

Challenges in Clinical Diagnosis of Williams-Beuren Syndrome in Sub-Saharan Africans: Case Reports from Cameroon

“…The typical deletion affects segments of 1.5 or 1.84 Mb, with variable frequencies of 95 and 5%, respectively [Schubert, 2009]. The clinical features observed in most patients include specific facial dysmorphism, a congenital heart defect with supravalvular aortic stenosis (SVAS) in about 75% of the cases, connective tissue disorders, mild to severe intellectual disability, endocrine anomalies, and a specific behavior characterized by overfriendliness, empathy and anxiety [Hobart et al, 2010;Morris, 2010a;Pober, 2010]. It has been found that co-morbidity of WBS and autistic disorder is frequent, resulting in a social communication impairment ranging from absence of verbal language to poor social relationships, in opposition to the classical behavioral phenotype of WBS [Tordjman et al, 2012].…”