The p.Ala510Val variant in the SPG7 gene: re-assessing the pathogenic significance of a ‘benign’ polymorphism

Abstract

Spastic paraplegia type 7 (SPG7) is characterised by adult-onset, progressive bilateral lower limb weakness and spasticity. SPG7 is inherited in an autosomal recessive manner and is due to mutations within the SPG7 gene. We sequenced the SPG7 gene as part of the diagnostic work-up for hereditary spastic paraparesis (HSP) in a large consanguineous sibship. We detected homozygosity for the variant p.Ala510Val in all affected individuals. This variant has historically been clas-sified as a non-functional polymorphism, but has more recently been shown to segregate with disease in some families. In light of the history of consanguinity and the large number of genes responsible for HSP, we undertook homozygosity mapping of all sibs using a high density single nucleotide polymorphism (SNP) array. We detected a long contiguous stretch of homozygosity on chromosome 16 (including the SPG7 gene) in each of the four affected individuals, which was not shared by eight unaffected siblings. Our data, together with predictions made by bioinformatic programmes, suggest that the p.Ala510Val variant is a pathogenic mutation. This case raises questions regarding the weight that should be placed on the classification given to variants in large population databases and what type of review procedure a diagnostic laboratory requires to ensure that updated classifications are not overlooked.