A biallelic variant of DCAF13 implicated in a neuromuscular disorder in humans.

Neuromuscular disorders encompass a broad range of phenotypes and genetic causes. We investigated a consanguineous family in which multiple patients had a neuromuscular disorder characterized by a waddling gait, limb deformities, muscular weakness and facial palsy. Exome sequencing was completed on the DNA of three of the four patients. We identified a novel missense variant in DCAF13, ENST00000612750.5, NM_015420.7, c.907 G > A;p.(Asp303Asn), ENST00000616836.4, NM_015420.6, c.1363 G > A:p.(Asp455Asn) (rs1209794872) segregating with this phenotype; being homozygous in all four affected patients and heterozygous in the unaffected individuals. The variant was extremely rare in the public databases (gnomAD allele frequency 0.000007081); was absent from the DNA of 300 ethnically matched controls and affected an amino acid which has been conserved across 1-2 billion years of evolution in eukaryotes. DCAF13 contains three WD40 domains and is hypothesized to have roles in both rRNA processing and in ubiquitination of proteins. Analysis of DCAF13 with the p.(Asp455Asn) variant predicted that the amino acid change is deleterious and affects a β-hairpin turn, within a WD40 domain of the protein which may decrease protein stability. Previously, a heterozygous variant of DCAF13 NM_015420.6, c.20 G > C:p.(Trp7Ser) with or without a heterozygous missense variant in CCN3, was suggested to cause inherited cortical myoclonic tremor with epilepsy. In addition, a heterozygous DCAF13 variant has been associated with autism spectrum disorder. Our study indicates a potential role of biallelic DCAF13 variants in neuromuscular disorders. Screening of additional patients with similar phenotype may broaden the allelic and phenotypic spectrum due to DCAF13 variants.