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

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