Rare Inherited and De Novo CNVs Reveal Complex Contributions to ASD Risk in Multiplex Families

Abstract

Rare mutations, including copy-number variants (CNVs), contribute significantly to autism spectrum disorder (ASD) risk. Although their importance has been established in families with only one affected child (simplex families), the contribution of both de novo and inherited CNVs to ASD in families with multiple affected individuals (multiplex families) is less well understood. We analyzed 1,532 families from the Autism Genetic Resource Exchange (AGRE) to assess the impact of de novo and rare CNVs on ASD risk in multiplex families. We observed a higher burden of large, rare CNVs, including inherited events, in individuals with ASD than in their unaffected siblings (odds ratio [OR] = 1.7), but the rate of de novo events was significantly lower than in simplex families. In previously characterized ASD risk loci, we identified 49 CNVs, comprising 24 inherited events, 19 de novo events, and 6 events of unknown inheritance, a significant enrichment in affected versus control individuals (OR = 3.3). In 21 of the 30 families (71%) in whom at least one affected sibling harbored an established ASD major risk CNV, including five families harboring inherited CNVs, the CNV was not shared by all affected siblings, indicating that other risk factors are contributing. We also identified a rare risk locus for ASD and language delay at chromosomal region 2q24 (implicating NR4A2) and another lower-penetrance locus involving inherited deletions and duplications of WWOX. The genetic architecture in multiplex families differs from that in simplex families and is complex, warranting more complete genetic characterization of larger multiplex ASD cohorts.

De Novo Coding Variants Are Strongly Associated with Tourette Disorder

“…Of note, the ascertainment strategies used in both TD cohorts did not restrict to apparently simplex families, as was done in the SSC. Given the evidence for an increased burden of de novo variation in simplex versus multiplex families in ASD (e.g., Leppa et al, 2016), it would be reasonable to hypothesize that the current analysis may underestimate the rate ratios for de novo variants in simplex TD families.…”

WWOX, the FRA16D gene: A target of and a contributor to genomic instability

“…Several of these CNVs were recently reported by Leppa et al in which they analyzed 1532 families to assess the impact of CNVs on the risk of ASD in families with multiple affected individuals. They observed both deletion and duplication of inherited variants spanning WWOX in 9 affected children, with very high odds ratio . Even though some of the duplications shown in Figure of individuals with ASD extend 5′ upstream of WWOX (none >0.5 Mbp), Leppa et al concluded that WWOX is the target of a rare low‐penetrance ASD associated locus .…”

“…They observed both deletion and duplication of inherited variants spanning WWOX in 9 affected children, with very high odds ratio . Even though some of the duplications shown in Figure of individuals with ASD extend 5′ upstream of WWOX (none >0.5 Mbp), Leppa et al concluded that WWOX is the target of a rare low‐penetrance ASD associated locus . In another recent report, Mignot et al identified deleterious WWOX deletions in children affected with infantile epileptic encephalopathy (EIEE28, OMIM: 616211) in families where either both parents were carriers of heterozygous WWOX copy number deletions or one parent harbored a heterozygous copy number deletion and the other parent a heterozygous loss of function WWOX point mutation .…”

Motor Stereotypies: A Pathophysiological Review

“…In light of these findings, it is hypothesized that detection of both inherited and spontaneous ( de novo ) mutations could be highly productive approaches to gene discovery, similar to the utility of these approaches in prior studies of ASD (Sanders et al, 2015; Leppa et al, 2016) and schizophrenia (Fromer et al, 2014; McCarthy et al, 2014). To date, no gene variants have been reported that increase the risk for stereotypies, yet these studies are underway in our lab and others.…”