Gonadal mosaicism in ARID1B gene causes intellectual disability and dysmorphic features in three siblings

Abstract

The gene encoding the AT-rich interaction domain-containing protein 1B (ARID1B) has recently been shown to be one of the most frequently mutated genes in patients with intellectual disability (ID). The phenotypic spectrums associated with variants in this gene vary widely ranging for mild to severe non-specific ID to Coffin-Siris syndrome. In this study, we evaluated three children from a consanguineous Emirati family affected with ID and dysmorphic features. Genomic DNA from all affected siblings was analyzed using CGH array and whole-exome sequencing (WES). Based on a recessive mode of inheritance, homozygous or compound heterozygous variants shared among all three affected children could not be identified. However, further analysis revealed a heterozygous variant (c.4318C>T; p.Q1440*) in the three affected children in an autosomal dominant ID causing gene, ARID1B. This variant was absent in peripheral blood samples obtained from both parents and unaffected siblings. Therefore, we propose that the most likely explanation for this situation is that one of the parents is a gonadal mosaic for the variant. To the best of our knowledge, this is the first report of a gonadal mosaicism inheritance of an ARID1B variant leading to familial ID recurrence.

Keywords: ARID1B; gonadal mosaicism; non-Mendelian inheritance; whole-exome sequencing.

FIG. 1

Pedigree of consanguineous family with three intellectual disable children. A: Pedigree of consanguineous family showing three affected children with intellectually disable and dysmorphic features. Circles and squares denote females and males respectively, filled symbols represent affected members, double lines denote consanguineous marriage, roman numbers indicate the first generation until their offspring, arabic numbers depict all participants in this study. B: Pictures of affected children showing the typical feature of ARID1B-related ID. B.a,b: showing abnormal head shape and low-set, posteriorly rotated, and abnormally shaped ears, low anterior hair line with thick eyebrows, broad nasal tip, large mouth with thick lower lip and hypertrichosis. B.c: shows shows short fingers. B:d: shows broad big toe. [Color figure can be seen in the online version of this article, available at http://wileyonlinelibrary.com/journal/ajmga]

FIG. 2

Molecular analysis of patients with ARID1B mutation. A: DNA chromatograms of ARID1B mutation compared to wild-type sequence. A.b: shows the heterozygous nonsense mutation (c.4318C>T) detected in the affected patients. A.a,c: show normal chromatograms in the parents. [Color figure can be seen in the online version of this article, available at http://wileyonlinelibrary.com/journal/ajmga]