Mutations in a new dynein/dynactin adaptor gene cause Dominant Congenital Spinal Muscular Atrophy (DCSMA) and Hereditary Spastic Paraplegia (HSP)

Abstract

DCSMA is an autosomal dominant disorder of developing anterior horn cells, which results in lower limb predominant weakness, and wasting. HSP is a later-onset disorder of corticospinal motor neurons, which is also lower limb predominant. In a collaboration established through the Genome Variant Database for Human Diseases, we used a combination of genome-wide SNP-based linkage analysis, whole exome sequencing, and comparison of clinical and MRI features with those of other genetically characterized forms of DCSMA, to identify four mutations in a new disease gene in six kindreds with DCSMA or HSP, or a DCSMA/HSP overlap syndrome. Several novel pathogenic-looking variants in additional kindred..