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In a comprehensive genetic investigation of a Sardinian multiplex family with autism spectrum disorder (ASD), a rare damaging missense variant in ARHGAP21 was identified alongside other postsynaptic density (PSD) protein-encoding genes. The implicated variant was observed in two affected siblings, supporting a potential role for ARHGAP21 in ASD susceptibility (PMID:30736458).
The genetic evidence is derived from a single family study where ARHGAP21 emerged as one of several candidate genes through whole exome sequencing and SNP array analysis. Although the cohort size is limited, the segregation of the variant in one additional affected relative within the pedigree adds supportive weight to the finding (PMID:30736458).
This finding aligns with the hypothesis that dysregulation of PSD proteins, which are crucial for synaptic formation and spine morphogenesis, may contribute to neurodevelopmental disorders such as ASD. In this study, ARHGAP21 was noted among a group of genes having rare, predicted damaging variants that may disrupt normal synaptic signalling.
Despite the promise of this observation, the current genetic evidence remains limited by the overall low number of probands. In the absence of independent replication studies or expanded cohorts, the clinical validity of ARHGAP21 as an ASD candidate is yet to be firmly established.
Furthermore, functional evidence directly linking ARHGAP21 to ASD pathophysiology is minimal. Although ARHGAP21 is known to be involved in cellular signaling pathways related to synaptic function, no dedicated functional assays have been reported in the context of ASD. This gap underscores the need for further experimental studies to assess the impact of the observed missense variant on protein function and neurodevelopment.
Taken together, the current evidence suggests a limited association between ARHGAP21 and autism spectrum disorder. While the identification of a rare damaging variant in a multiplex family is intriguing, additional genetic and functional studies are essential to validate its clinical utility. Key take‑home: ARHGAP21’s potential role in ASD should be considered in the broader framework of rare PSD gene variants, warranting further investigation for diagnostic and therapeutic development.
Gene–Disease AssociationLimitedA rare damaging missense variant in ARHGAP21 was identified in 2 probands from a single multiplex ASD family with segregation in one additional affected relative (PMID:30736458). Genetic EvidenceLimitedThe genetic evidence is based on a single family study where a rare variant in ARHGAP21 was observed alongside other candidate variants, providing preliminary support despite the small sample size (PMID:30736458). Functional EvidenceLimitedThere are no direct functional studies linking ARHGAP21 to ASD. While ARHGAP21’s role in PSD function suggests biological plausibility, further experimental validation is required. |