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

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 <i>CAPG</i>, <i>ELMOD3,</i> and <i>SH2D6</i> genes, in both siblings. <i>CAPG</i> encodes for a postsynaptic density (PSD) protein known to regulate spine morphogenesis and synaptic formation. The reduced <i>CAPG</i> 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 <i>CAPG</i> as a candidate gene for ASD. WES analysis led to the identification in both affected siblings of a rare frameshift mutation in <i>VDAC3</i>, 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: <i>PLXNA2</i>, <i>KCTD16</i>, <i>ARHGAP21,</i> and <i>SLC4A1</i>. This study identifies <i>CAPG</i> and <i>VDAC3</i> as candidate genes and provides additional support for genes encoding PSD proteins in ASD susceptibility.