Homozygous 2p11.2 deletion supports the implication of ELMOD3 in hearing loss and reveals the potential association of CAPG with ASD/ID etiology

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

“…Recently, a homozygous deletion affecting the last three exons of ELMOD3 , the entire CAPG gene, and the first non-coding exon of SH2D6 has been identified in a Tunisian ASD proband with ID and hearing impairment. The deletion is inherited from consanguineous parents, both heterozygous for the deletion [31]. No CNVs in this genomic region are present in 6639 European controls [32,33,34,35,36].…”

“…Genome-wide CNV analysis in a Sardinian multiplex family led to the identification of a rare genic heterozygous deletion on chromosome 2, involving the whole CAPG gene, the last coding exons of ELMOD3 and the first non-coding exon of SH2D6 , inherited by both affected siblings from the unaffected mother. 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.…”

“…Indeed, we can hypothesize that the injurious effect of inherited CAPG deletions can be modified by the specific genetic background of the carrier individual. Therefore, in the Tunisian ASD proband [31], the presence of CAPG homozygous deletion could be sufficient to determine the autistic phenotype, while, in the two ASD Sardinian siblings here described, the CAPG deletion might act in combination with the VDAC3 2 bp-frameshift deletion and/or with the other identified deleterious variants in the PSD genes ( PLXNA2 , KCTD16 , ARHGAP21, and SLC4A1 ). However, further studies are warranted to better clarify the role of CAPG, alone and in combination with the other identified PSD genes, in the impairment of synaptic homeostasis that is considered a common biological process associated with ASDs.…”

Homozygous deletion of 21q22.2 in a patient with hypotonia, developmental delay, cortical visual impairment, and retinopathy

“…Understanding the impact of homozygous deletion of genes without known impact on human physiology is more challenging, but often some inferences can be made based on knowledge of gene function. For example, the homozygous deletion of ELMOD3, CAPG and SH2D6 in a boy with autism spectrum disorder (ASD) lead to the proposition of absence of CAPG contributing to the ASD phenotype in the patient (Lahbib et al, 2019). Homozygous and heterozygous deletions in this region were identified in additional patients with ASD and resulted in the discovery of an abnormal fusion product of ELMOD3 and SH2D6 in a family with a heterozygous deletion (Loi et al, 2020).…”

ELMOD3‐SH2D6 gene fusion as a possible co‐star actor in autism spectrum disorder scenario

“…We identified a rare heterozygous 2p11.2 deletion, including the last coding exons of ELMOD3 , the entire CAPG gene and the first non‐coding exon of SH2D6 , in both ASD siblings inherited from their unaffected mother (Figure A). Interestingly, two similar heterozygous and one homozygous deletions have been reported in three independent ASD families, supporting the clinical relevance of this locus for ASD (Figure A).…”