Pathogenic missense variants altering codon 336 of GARS1 lead to divergent dominant phenotypes

Alayne P. Meyer, Megan E. Forrest, Stefan Nicolau, Wojciech Wiszniewski, Mary Pat Bland, Chang Yong Tsao, Anthony Antonellis, Nicolas J. Abreu

Research output: Contribution to journalArticlepeer-review

Abstract

Heterozygosity for missense variants and small in-frame deletions in GARS1 has been reported in patients with a range of genetic neuropathies including Charcot−Marie−Tooth disease type 2D (CMT2D), distal hereditary motor neuropathy type V (dHMN-V), and infantile spinal muscular atrophy (iSMA). We identified two unrelated patients who are each heterozygous for a previously unreported missense variant modifying amino-acid position 336 in the catalytic domain of GARS1. One patient was a 20-year-old woman with iSMA, and the second was a 41-year-old man with CMT2D. Functional studies using yeast complementation assays support a loss-of-function effect for both variants; however, this did not reveal variable effects that might explain the phenotypic differences. These cases expand the mutational spectrum of GARS1-related disorders and demonstrate phenotypic variability based on the specific substitution at a single residue.

Original languageEnglish (US)
Pages (from-to)869-876
Number of pages8
JournalHuman mutation
Volume43
Issue number7
DOIs
StatePublished - Jul 2022

Keywords

  • Charcot−Marie−Tooth disease
  • GARS1
  • complementation assay
  • missense variant
  • spinal muscular atrophy

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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