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In a cohort of 24 simplex families, whole‐exome sequencing identified a single de novo splicing variant in XRCC6 in a sporadic Autism Spectrum Disorder (ASD) proband. The heterozygous variant abolishes the canonical 5′ splice donor of intron 9, resulting in intron retention, a premature stop codon, and markedly reduced XRCC6 transcript and protein levels (PMID:31827253). No additional affected relatives were reported, and no recurrent or founder variants have been described to date.
Functional studies in patient‐derived cells confirmed intron 9 retention and diminished XRCC6 expression, consistent with a loss‐of‐function mechanism impacting nonhomologous end joining. XRCC6 encodes Ku70, a core DNA double‐strand break repair factor whose deficiency perturbs genomic stability and neurodevelopmental pathways. Taken together, current evidence is insufficient to establish a definitive gene–disease relationship, and replication in independent cohorts is required. Key take‐home: at present, XRCC6 disruption is a limited candidate for ASD risk and warrants further case series and functional validation.
Gene–Disease AssociationLimitedSingle de novo splicing variant in one proband with transcript disruption ([PMID:31827253]). Genetic EvidenceLimitedOne de novo variant in a sporadic ASD case; no segregation or recurrence ([PMID:31827253]). Functional EvidenceLimitedPatient cell assays demonstrate intron retention and reduced XRCC6 expression consistent with loss of function ([PMID:31827253]). |