Identification of a rare deletion encompassing ELMOD3 and CAPG in two siblings with Autism Spectrum Disorder

Autism Spectrum Disorder (ASD) is a severe neurodevelopmental condition with highly complex genetic predisposition. Recent discoveries have highlighted the importance of both sequence and structural rare variations in ASD susceptibility. In particular, focusing on rare copy number variants (CNVs) has already been highly productive in uncovering an increasing number of specific genes and chromosomal intervals conferring risk to ASD. During a genome-wide CNV scan using a multi-algorithm approach on 9 multiplex ASD families from Sardinia, we identified a rare genic deletion of ~37 Kb, transmitted from the unaffected mother to both affected siblings. This deletion includes the entire CAPG gene and the last coding exons of ELMOD3. CAPG encodes a member of the gelsolin/villin family of actin-regulatory proteins, that might be involved in control of dendritic spine shape. ELMOD3 belongs to the engulfment and cell motility (ELMO) family, with recently proposed functional links to sound perception and actin cytoskeleton. No deletions involving this genomic region were found in 4768 controls from published high resolution SNP-array data, while other two deletions encompassing CAPG and ELMOD3 have been reported in two subjects with ASD, suggesting that CAPG and/or ELMOD3 haploinsufficiency may have clinical relevance to ASD. In order to test this hypothesis together with a recessive model of inheritance, we first excluded that this deletion is a common polymorphism in Sardinia, then we performed expression and mutation analysis of both genes in the discovery pedigree, and a further clinical evaluation of all family members. Grant references: Fondazione Banco di Sardegna, Kyulan Family Foundation