CNTN6 mutations are risk factors for abnormal auditory sensory perception in autism spectrum disorders

Abstract

Contactin genes CNTN5 and CNTN6 code for neuronal cell adhesion molecules that promote neurite outgrowth in sensory-motor neuronal pathways. Mutations of CNTN5 and CNTN6 have previously been reported in individuals with autism spectrum disorders (ASDs), but very little is known on their prevalence and clinical impact. In this study, we identified CNTN5 and CNTN6 deleterious variants in individuals with ASD. Among the carriers, a girl with ASD and attention-deficit/hyperactivity disorder was carrying five copies of CNTN5. For CNTN6, both deletions (6/1534 ASD vs 1/8936 controls; P=0.00006) and private coding sequence variants (18/501 ASD vs 535/33480 controls; P=0.0005) were enriched in individuals with ASD. Among the rare CNTN6 variants, two deletions were transmitted by fathers diagnosed with ASD, one stop mutation CNTN6W923X was transmitted by a mother to her two sons with ASD and one variant CNTN6P770L was found de novo in a boy with ASD. Clinical investigations of the patients carrying CNTN5 or CNTN6 variants showed that they were hypersensitive to sounds (a condition called hyperacusis) and displayed changes in wave latency within the auditory pathway. These results reinforce the hypothesis of abnormal neuronal connectivity in the pathophysiology of ASD and shed new light on the genes that increase risk for abnormal sensory perception in ASD.

Intragenic CNTNAP2 Deletions: A Bridge Too Far

“…Commensurate with its negative association with ASD, mice with a homozygous loss of Cntn4 did not show any significant ASD-related behavioral disturbances [Poot, 2014;Molenhuis et al, 2016]. In contrast, patients with CNVs of or SNVs in the coding sequence of CNTN5 and CNTN6 show auditory phenotypes, such as hyperacusis [Mercati et al, 2016]. In 14 out of 3,724 patients with neurodevelopmental disorders, such as developmental delay, ASD, seizures, and ADHD, CNVs of CNTN6 were found [Hu et al, 2015].…”

“…Since roughly 10% of all patients with ID carry more than a single CNV, a genome-wide screen should be performed to search for additional CNVs after a first one has been detected [Poot et al, 2011;Girirajan et al, 2012]. NANC is not restricted to CNVs, but also applies to single nucleotide variants (SNVs) causing lossof-function mutations [Leblond et al, 2012;Mercati et al, 2016].…”

“…Indeed, an association of a locus may also involve mechanisms not directly related to the protein-coding part of a nearby gene, but for instance an eQTL [Nicolae et al, 2010]. Nevertheless, in a survey of 2 large cohorts of patients with ASD, a single patient was found to carry mutations in both CNTNAP2 and CNTN6 , which he inherited from his healthy mother [Mercati et al, 2016]. Furthermore, the association of CNTNAP2 with CNTN6 was not confirmed in terms of a physical interaction of Caspr2 with CNTN6 [Rubio-Marrero et al, 2016].…”

“…These findings indicate that CNTNAP2 is involved in the ontogeny and function of neural systems participating in auditory processing. Conversely, disruption of these neural systems during development may contribute to the atypical language phenotype seen in some patients with ASD [Boddaert et al, 2003;Ceponiene et al, 2003;Poot et al, 2010;Truong et al, 2015;Mercati et al, 2016].…”

Intragenic Deletions May Involve Enhancer Sequences and Alter <b><i>CNTNAP2</i></b> Expression

“…Interestingly, in a cohort of children with autism spectrum disorders, risk alleles of CNTNAP2 and CNTN6 occurred more frequently than expected, assuming random segregation [Poot, 2014]. In an independent cohort of patients with autism spectrum disorders, a single patient inherited mutated alleles of CNTNAP2 and CNTN6 from each parent [Mercati et al, 2017]. Although a mechanistic basis for these observations has not yet been proposed, they implicate differences in exonand allele-specific CNTNAP2 expression in the predisposition to some neurodevelopmental disorders.…”