Sequencing Aids Diagnosis of Neurometabolic Disease
(HealthDay News) — Exome sequencing improves the ability to identify potential nuclear gene mutations in patients with biochemically defined defects affecting multiple mitochondrial respiratory chain complexes, according to a study published in the July 2 issue of the Journal of the American Medical Association.
Robert W. Taylor, PhD, from Newcastle University in the United Kingdom, and colleagues studied 53 patients (referred between 2005–2012) with biochemical evidence of multiple respiratory chain complex defects but no primary pathogenic mitochondrial DNA mutation. Whole-exome sequencing was performed with variant validation by Sanger sequencing.
The researchers found that presumptive causal variants were identified in 28 patients (53%) and possible causal variants were identified in four patients (8%). Together, these variants involved 18 different genes, including recurrent mutations in RMND1, AARS2, and MTO1, each on a haplotype background consistent with a shared founder allele. Additionally, potential novel mutations in four possible mitochondrial disease genes were seen (VARS2, GARS, FLAD1, and PTCD1). Deafness and renal involvement were associated with RMND1, while cardiomyopathy was associated with AARS2 and MTO1. Atypical clinical features were present in some patients with mutations. The underlying genetic basis could not be identified in 21 patients (40%).
"Additional study is required in independent patient populations to determine the utility of this approach in comparison with traditional diagnostic methods," the authors write.