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This summary details the association between the gene DCAF13 (HGNC:24535) and a neuromuscular disorder (MONDO_0019056). Evidence originates primarily from a consanguineous family where a neuromuscular phenotype—including limb abnormalities, a waddling gait, muscle weakness, and facial palsy—was observed. The clinical presentation is consistent with a discrete neuromuscular syndrome (PMID:36797467).
Exome sequencing revealed biallelic variants in DCAF13, with genetic analysis showing that all four affected individuals were homozygous for a novel missense variant. Notably, the variant c.1363>A (p.Asp455Asn) was identified and validated through segregation analysis in the affected family members (PMID:36797467).
The genetic evidence is compelling. In this study, the variant was shown to segregate in an autosomal recessive manner, with heterozygous carriers being unaffected. This robust segregation across four affected individuals supports a strong gene-disease association. The missense change affects a highly conserved residue, adding further weight to its pathogenicity (PMID:36797467).
Functional assessments predict that the p.Asp455Asn change disrupts a β-hairpin turn within a WD40 domain that is crucial for protein stability. This alteration is consistent with the proposed mechanism of pathogenicity, namely, a loss or reduction of normal protein function that may impair roles in rRNA processing and ubiquitination, processes essential for neuromuscular integrity (PMID:36797467).
It is noteworthy that DCAF13 has previously been implicated in other neurological conditions such as cortical myoclonic tremor with epilepsy and autism spectrum disorder. However, the biallelic nature and consistent segregation of the variant in this neuromuscular cohort clearly delineate a distinct phenotypic and inheritance pattern, thereby reinforcing the specificity of this association (PMID:36797467).
In conclusion, the convergence of robust segregation data, consistent clinical presentation, and supportive functional predictions positions the gene-disease association for DCAF13 in neuromuscular disorders as strong. This evidence is valuable for diagnostic decision‑making, commercial use, and future publication, with the key take‑home message that biallelic DCAF13 variants represent a promising molecular marker for neuromuscular disease.
Gene–Disease AssociationStrongFour affected individuals in a consanguineous family exhibit biallelic DCAF13 variants with a consistent neuromuscular phenotype and robust segregation evidence (PMID:36797467). Genetic EvidenceStrongThe report identifies two missense variants with one, c.1363>A (p.Asp455Asn), segregating in all four affected individuals. This autosomal recessive pattern, coupled with the low allele frequency and high conservation of the affected residue, underpins strong genetic evidence (PMID:36797467). Functional EvidenceModerateIn silico analyses predict that the p.Asp455Asn variant disrupts a critical β‑hairpin turn in a WD40 domain, likely impairing protein stability and function in rRNA processing and ubiquitination, which aligns with the neuromuscular phenotype (PMID:36797467). |