Use of focused exome sequencing in adult-onset leukodystrophy to identify new genes and mutations

Abstract

BackgroundThe leukodystrophies are a group of disorders that selectively involve degeneration of the white matter of the central nervous system. Recent discoveries in genetics have expanded our knowledge of hereditary leukodystrophies. We aimed to investigate the phenotypic spectrum of leukodystrophy genes without selection bias, thereby expanding the genotype–phenotype correlation. Methods18 patients with adult-onset, undiagnosed leukodystrophy were analysed with focused exome sequencing (SureSelect Focused Exome, Agilent Technologies, Santa Clara CA, USA). Suspected mutations were subsequently confirmed by Sanger sequencing. FindingsWe made a genetic diagnosis in six cases. Interestingly, in this adult-onset cohort, only one individual was found to have a mutation in an autosomal dominant gene (CSF1R) with the remainder with homozygous or compound heterozygous variants in the following autosomal recessive genes: POLR3A, EIF2B5, DARS2, MRPS22, and TREM2. No gene was responsible for more than one case, reflecting the extreme clinical and genetic heterogeneity of adult-onset leukodystrophy. These genes are responsible for mitochondrial health, RNA transcription, and microglial signalling. InterpretationFocused exome sequencing is a non-hypothesis driven approach allowing for association of clinical phenotype with otherwise unsuspecting molecular pathways. It is a cost-effective method that should be considered early in the diagnostic process, avoiding time and money spent on other more invasive investigations. This is of paramount importance for the patient in terms of early treatment and appropriate genetic counselling. FundingNational Institute for Health Research, Leonard Wolfson Experimental Neurology Centre.