Exome Sequencing Links Corticospinal Motor Neuron Disease to Common Neurodegenerative Disorders

TLDR

Hereditary spastic paraplegias are neurodegenerative motor neuron diseases marked by progressive loss of corticospinal tract function, yet only a fraction of cases receive a genetic diagnosis and a comprehensive global view is lacking. The study aimed to identify novel HSP genes using whole‑exome sequencing combined with network analysis and to validate them functionally or genetically. Whole‑exome sequencing and network analysis were employed to discover and validate 18 novel putative HSP genes. Mutations in the newly identified genes implicate cellular transport, nucleotide metabolism, and synapse/axon development pathways, link HSP to other neurodegenerative disorders, and reveal additional candidate genes, three of which were mutated in the cohort.

Abstract

Hereditary spastic paraplegias (HSPs) are neurodegenerative motor neuron diseases characterized by progressive age-dependent loss of corticospinal motor tract function. Although the genetic basis is partly understood, only a fraction of cases can receive a genetic diagnosis, and a global view of HSP is lacking. By using whole-exome sequencing in combination with network analysis, we identified 18 previously unknown putative HSP genes and validated nearly all of these genes functionally or genetically. The pathways highlighted by these mutations link HSP to cellular transport, nucleotide metabolism, and synapse and axon development. Network analysis revealed a host of further candidate genes, of which three were mutated in our cohort. Our analysis links HSP to other neurodegenerative disorders and can facilitate gene discovery and mechanistic understanding of disease.