Analysis of a Sardinian Multiplex Family with Autism Spectrum Disorder Points to Post-Synaptic Density Gene Variants and Identifies CAPG as a Functionally Relevant Candidate Gene.

Elena Bacchelli,Giuseppe Doneddu,Cinzia Cameli,Elena Maestrini,Ana Vega Benedetti,Elena Bonora,Sandra Mattu,Patrizia Zavattari,Loredana Moi,Antonio Fadda,Rita Chessa,Eleonora Loi,Sylvain Blois,Roberta Fadda

doi:10.3390/jcm8020212

Abstract

Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders with high heritability, although their underlying genetic factors are still largely unknown. Here we present a comprehensive genetic characterization of two ASD siblings from Sardinia by genome-wide copy number variation analysis and whole exome sequencing (WES), to identify novel genetic alterations associated with this disorder. Single nucleotide polymorphism (SNP) array data revealed a rare microdeletion involving CAPG, ELMOD3, and SH2D6 genes, in both siblings. CAPG encodes for a postsynaptic density (PSD) protein known to regulate spine morphogenesis and synaptic formation. The reduced CAPG mRNA and protein expression levels in ASD patients, in the presence of hemizygosity or a particular genetic and/or epigenetic background, highlighted the functional relevance of CAPG as a candidate gene for ASD. WES analysis led to the identification in both affected siblings of a rare frameshift mutation in VDAC3, a gene intolerant to loss of function mutation, encoding for a voltage-dependent anion channel localized on PSD. Moreover, four missense damaging variants were identified in genes intolerant to loss of function variation encoding for PSD proteins: PLXNA2, KCTD16, ARHGAP21, and SLC4A1. This study identifies CAPG and VDAC3 as candidate genes and provides additional support for genes encoding PSD proteins in ASD susceptibility.

Highlights

Autism spectrum disorder (ASD) (Mendelian Inheritance in Man (MIM) 209850) is a neurodevelopmental disorder characterized by early onset in childhood, atypical and repetitive behaviors and impairments in communication and reciprocal social interaction
During a genome-wide copy number variants (CNVs) scan using a multi-algorithm approach on one multiplex family with ASD from Sardinia, we identified a rare genic heterozygous deletion of ~37 kb, involving the whole CAPG gene, the last coding exons of ELMOD3 and the first non-coding exon of SH2D6
The deletion encompasses a CNV stable region of genome [22] and has not been reported in controls, while similar deletions spanning CAPG-ELMOD3-SH2D6 have been detected in three independent ASD families, in the heterozygous [30] and the homozygous [31] state, suggesting that this deletion might be involved in ASD susceptibility

Summary

Introduction

Autism spectrum disorder (ASD) (Mendelian Inheritance in Man (MIM) 209850) is a neurodevelopmental disorder characterized by early onset in childhood, atypical and repetitive behaviors and impairments in communication and reciprocal social interaction. The phenotype of ASDs is extremely heterogeneous, with individual differences in a wide range of symptoms and severity [1,2,3,4]. Autism is more prevalent in male individuals, with an overall male-to-female ratio close to 3:1 [6]. Multiple lines of evidence support the strong role of genetics and heritability in the etiology of ASDs [2,3,4]. In line with the highly heterogeneous phenotypic manifestations, the underlying genetic architecture of ASD is complex, with a combined contribution of both common and rare forms of genetic variations [7]

Methods

Results

Conclusion