Mapping of partially overlapping de novo deletions across an autism susceptibility region (AUTS5) in two unrelated individuals affected by developmental delays with communication impairment

Abstract

Autism is a neurodevelopmental disorder characterized by deficits in reciprocal social interaction and communication, and repetitive and stereotyped behaviors and interests. Previous genetic studies of autism have shown evidence of linkage to chromosomes 2q, 3q, 7q, 11p, 16p, and 17q. However, the complexity and heterogeneity of the disorder have limited the success of candidate gene studies. It is estimated that 5% of the autistic population carry structural chromosome abnormalities. This article describes the molecular cytogenetic characterization of two chromosome 2q deletions in unrelated individuals, one of whom lies in the autistic spectrum. Both patients are affected by developmental disorders with language delay and communication difficulties. Previous karyotype analyses described the deletions as [46,XX,del(2)(q24.1q24.2)dn]. Breakpoint refinement by FISH mapping revealed the two deletions to overlap by approximately 1.1Mb of chromosome 2q24.1, a region which contains just one gene—potassium inwardly rectifying channel, subfamily J, member 3 (KCNJ3). However, a mutation screen of this gene in 47 autistic probands indicated that coding variants in this gene are unlikely to underlie the linkage between autism and chromosome 2q. Nevertheless, it remains possible that variants in the flanking genes may underlie evidence of linkage at this locus. © 2009 Wiley‐Liss, Inc.

Genetic Variation in the Inwardly Rectifying K⁺ Channel Subunits <i>KCNJ3</i> (<i>GIRK1</i>) and <i>KCNJ5</i> (<i>GIRK4</i>) in Patients with Sinus Node Dysfunction

“…Interestingly, a recent paper demonstrated an allele frequency similar to ours – a synonymous mutation was found in 1 of 47 autistic patients screened for KCNJ3 mutations. In line with our conclusions, this led the authors to speculate that KCNJ3 is probably not involved in the pathogenesis of autism [19]. Taken together, our data do not indicate that our variants associate with SND or account for the phenotype in our population.…”

Investigation of TBR1 Hemizygosity: Four Individuals with 2q24 Microdeletions

“…Deletions of various sizes spanning the 2q21q31 region have been reported in over 100 cases and are associated with a broad spectrum of phenotypic features [Pereira et al, 2004;Langer et al, 2006;Pescucci et al, 2007;Davidsson et al, 2008;Newbury et al, 2009;Chen et al, 2010;Krepischi et al, 2010;Takatsuki et al, 2010;Magri et al, 2011;Palumbo et al, 2012], including seizure disorder [Grosso et al, 2008]. Substantial evidence indicates that the sodium channel (SCN) ␣ subunit genes of the 2q24.3 region, in particular SCN1A , induce the seizure phenotype when mutated or deleted [Davidsson et al, 2008;Escayg and Goldin, 2010], although there is evidence for the contribution of SLC4A10 at 2q24.2 to a milder seizure phenotype when deleted [Krepischi et al, 2010].…”

Developing Synaesthesia

“…A whole-genome linkage scan and a family-linkage analysis in a sample of 43 multiplex families with auditory-visual synesthesia did not confirm this hypothesis . Instead the study suggested that synesthesia may be traceable to a region on chromosome 2 (2q24.1) that has been implicated in autism (Newbury et al, 2009), indicating that there may be genetic link between developmental synesthesia and autism.…”