Rare De Novo and Transmitted Copy-Number Variation in Autistic Spectrum Disorders

Abstract

To explore the genetic contribution to autistic spectrum disorders (ASDs), we have studied genomic copy-number variation in a large cohort of families with a single affected child and at least one unaffected sibling. We confirm a major contribution from de novo deletions and duplications but also find evidence of a role for inherited "ultrarare" duplications. Our results show that, relative to males, females have greater resistance to autism from genetic causes, which raises the question of the fate of female carriers. By analysis of the proportion and number of recurrent loci, we set a lower bound for distinct target loci at several hundred. We find many new candidate regions, adding substantially to the list of potential gene targets, and confirm several loci previously observed. The functions of the genes in the regions of de novo variation point to a great diversity of genetic causes but also suggest functional convergence.

Autism throughout genetics: Perusal of the implication of ion channels

“…Thanks to the comparative genomic hybridization (CGH) technique or SNPs array, CNVs were also found in multiple chromosomal regions at 1q21.1, 16p11.2, 17q12, and 22q11.2 (Jacquemont et al., 2006; Marshall et al., 2008; Matsunami et al., 2013; O'Roak et al., 2012; Pinto et al., 2010; Sebat et al., 2007). Further studies supported the association with ASD of two recurrent de novo CNVs at 16p11.2 (duplication and deletion) and 7q11.23 (duplication; Levy et al., 2011; Sanders Stephan et al., 2011). The chromosomal deletion found at 7q11.23 has been linked to William's syndrome, which includes intellectual disabilities, facial dysmorphic features, congenital heart defect, and transient hypercalcemia.…”

Autism genetics: searching for specificity and convergence

“…Over the past several years, genome-wide association studies (GWAS) have revealed a handful of common alleles of modest effect size likely to contribute to ASD [46-48]. Analysis of CNV has additionally implicated rare genomic structural changes, both de novo and inherited, of large effect size [20,21,49-52]. Most recently, exome sequencing has lent insight into the contribution of de novo SNVs [22-25].…”

“…For simplicity, these models are presented as distinct categories, whereas in reality ASD risk is likely to be represented by a more continuous distribution of risk architecture. A single asterisk indicates that there is evidence to suggest that de novo CNVs in unaffected controls are smaller [21,51,52] and less gene-rich [20,21] than in people with ASD. A double asterisk indicates that there is conflicting evidence for increased oligogenic heterozygosity [25,156].…”

“…These studies have shed light on the contribution of rare CNVs to ASD pathophysiology, with several themes emerging. First, in all five studies that examined inherited CNVs, inherited CNVs were equally prevalent in individuals with ASD as in controls [20,21,50,51]. Although one study reports a 1.19-fold higher number of CNVs ( de novo and inherited) in cases than in controls, this signal is driven by the contribution of rare de novo CNVs, as removing these CNVs from the analysis results in an equal distribution of CNVs between cases and controls [52].…”

“…These include genetic copy number variation (CNV; duplicated or deleted regions of the genome greater than 1 kb [17]), syndromic forms of autism (ASD that occurs within a defined syndrome, such as fragile × syndrome), and single gene and metabolic disorders [18,19]. Recent studies based on CNV and single nucleotide variant (SNV) data put the number of ASD-implicated genes at between 200 and 1,000 [20-25], and multiple modes of inheritance have been proposed [26-28]. In addition, many ASD-implicated genes are also associated with other neuropsychiatric disorders, including schizophrenia, ADHD, epilepsy, and intellectual disability [22,29-40], and none are specific for autism, suggesting that additional modifying factors dictate the clinical outcome of having disruptions in a specific gene.…”