Objective: To elucidate the underlying genetic cause of dSMA in a Chinese family with two affected siblings.

Background: Distal spinal muscular atrophy (dSMA), also called distal hereditary motor neuropathy (dHMN), is a rare clinically and genetically heterogeneous group of inherited disorders characterized by progressive distal muscle weakness and wasting without sensory abnormalities. To date, at least 20 genes and 4 loci associated with dSMA have been reported. However, more than 65% of patients with dSMA have undiscovered genetic mutations.

Methods: Whole exome sequencing was performed on two affected siblings, and Sanger sequencing was done to validate and confirm segregation in available family members.

Results: The proband was found to have a novel homozygous c.1124G>A mutation of VRK1 exon 12 (NM_003384.2), producing a premature stop codon (p.W375X). The affected sister also harbored the same homozygous c.1124G>A mutation. The novel homozygous mutation in VRK1 completely co-segregated with the disease phenotype in the available family members.

Conclusions: A novel p.W375X nonsense mutation in the VRK1 gene is associated with autosomal recessive dSMA in a Chinese family. Our findings broaden the genetic spectrum of VRK1-associated dSMA and have implications for molecular diagnostics of dSMA. In addition, future functional studies would be needed to evaluate the pathogenicity of this novel mutation in dSMA.

References: 1. Renbaum P, Kellerman E, Jaron R, Geiger D, Segel R, Lee M, King MC, Levy-Lahad E. Spinal muscular atrophy with pontocerebellar hypoplasia is caused by a mutation in the VRK1 gene. Am J Hum Genet 2009; 85: 281-9. 2. Stoll M, Teoh H, Lee J, Reddel S, Zhu Y, Buckley M, Sampaio H, Roscioli T, Farrar M, Nicholson G. Novel motor phenotypes in patients with VRK1 mutations without pontocerebellar hypoplasia. Neurology 2016; 87: 65-70.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-novel-mutation-in-vrk1-associated-with-distal-spinal-muscular-atrophy/