FSCN1 as a Candidate Gene for Syndromic Intellectual Disability? Evidence From a Recurrent Variant in an Iranian Cohort.

Abstract

Intellectual disability (ID) is a genetically heterogeneous disorder, and many causative genes remain unidentified. FSCN1 encodes an actin-bundling protein essential for neuronal development, but its role in human neurodevelopmental disorders has not been clinically established. By revisiting data from a previously studied Iranian ID cohort, we identified two unrelated families carrying the same rare pathogenic missense variant in FSCN1 (c.665C>A; p.Ala222Asp). Affected individuals exhibited moderate to severe ID with consistent craniofacial features, including a prominent maxilla, long face, broad forehead, and thick lower lip. In silico tools predicted the variant as damaging and destabilizing, and the affected residue is highly conserved. This study provides the first clinical evidence linking FSCN1 to syndromic ID with craniofacial anomalies. The craniofacial features observed in our patients are consistent with experimental evidence from animal models. Together with supportive data from animal models, our findings suggest FSCN1 as a candidate gene for rare or ultra-rare forms of ID and warrant further functional studies to elucidate its precise pathogenic mechanisms.