Identification of a functional rare variant in autism using genome-wide screen for monoallelic expression

Abstract

Recent work has led to the identification of several susceptibility genes for autism spectrum disorder (ASD) and an increased appreciation of the importance of rare and de novo mutations. Some of the mutations may be very hard to detect using current strategies, especially if they are located in regulatory regions. We present a new approach to identify functional mutations that exploit the fact that many rare mutations disrupt the expression of genes from a single parental chromosome. The method incorporates measurement of the relative expression of the two copies of a gene across the genome using single nucleotide polymorphism arrays. Allelic expression has been successfully used to study common regulatory polymorphisms; however, it has not been implemented as a screening tool for rare mutation. We tested the potential of this approach by screening for monoallelic expression in lymphoblastoid cell lines derived from a small ASD cohort. After filtering regions shared across multiple samples, we identified genes showing monoallelic expression in specific ASD samples. Validation by quantitative sequencing demonstrated that the genes (or only part of them) are monoallelic expressed. The genes included both previously suspected risk factors for ASD and novel candidates. In one gene, named autism susceptibility candidate 2 (AUTS2), we identified a rare duplication that is likely to be the cause of monoallelic expression. Our results demonstrate the ability to identify rare regulatory mutations using genome-wide allelic expression screens, capabilities that could be expanded to other diseases, especially those with suspected involvement of rare dominantly acting mutations.

An inside job: how endosomal Na+/H+ exchangers link to autism and neurological disease

“…Homozygosity mapping, microarray, and sequencing data from families of autism patients with shared ancestry showed a chromosomal deletion in a potentially regulatory non-coding region upstream of SLC9A9 (Morrow et al, 2008). Other autism associated deletion mutations involving NHE9 have been also reported in the literature (Ben-David et al, 2011; Wagle and Holder, 2014). Furthermore, in non-consanguineous autistic pedigrees several rare coding variants and a non-sense mutation truncating the last predicted extracellular loop of the 10–12 membrane-spanning NHE9 protein were identified in patients with autism and epilepsy (Morrow et al, 2008).…”

Detection of copy-number variation in AUTS2 gene by targeted exonic array CGH in patients with developmental delay and autistic spectrum disorders

“…25 Haploinsufficiency of AUTS2 (three reports of apparently balanced translocation and two reports of inversion) has been associated with ASDs, ID, seizures, and attention deficit hyperactivity disorder. [26][27][28][29][30][31]34 Sultana et al 30 reported monozygotic twins with ID and autism with an apparently balanced t(7;20) (q11.2; p11.2) that disrupted AUTS2. Kalscheuer et al 32 described translocations involving AUTS2 in three unrelated individuals with mild to moderate ID.…”

“…26,29 Ben-David et al 26 reported a duplication of 140 kb in size, involving exon 5 that resulted in monoallelic expression of AUTS2 in a patient with ASDs. Mefford et al 29 used whole-genome oligonucleotide aCGH in a cohort of 517 individuals with idiopathic epilepsy and found two patients with small intragenic deletions.…”

Cytoskeletal Regulation by AUTS2 in Neuronal Migration and Neuritogenesis

“…Thereafter, more than 30 unrelated patients with multiple neuropsychiatric disorders such as ASD, intellectual disability (ID), attention deficit hyperactivity disorder, dyslexia, and epilepsy as well as developmental delay (DD), visual impairment, and microcephaly have been shown to carry distinct heterozygous disruptions of the AUTS2 locus (Bakkaloglu et al, 2008;Ben-David et al, 2011;Elia et al, 2010;Glessner et al, 2009;Huang et al, 2010;Kalscheuer et al, 2007;Pinto et al, 2010;Talkowski et al, 2012). In addition, 24 exonic microdeletions were identified in the AUTS2 gene in individuals with various psychiatric disorders (Beunders et al, 2013).…”