Glycyl tRNA Synthetase (GARS) Gene Variant Causes Distal Hereditary Motor Neuropathy V

Abstract

Distal hereditary motor neuropathies (dHMN) are a rare heterogeneous group of inherited disorders specifically affecting the motor axons, leading to distal limb neurogenic muscular atrophy. The GARS gene has been identified as a causative gene responsible for clinical features of dHMN type V in families from different ethnic origins and backgrounds. We present the first cohort of family members of Nigerian descent with a novel heterozygous p.L272R variant on the GARS gene. We postulate that this variant is the cause of dHMN-V in this family, leading to variable phenotypical expressions that are earlier than reported in previous cases. The exact cause for the observed clinical heterogeneity within the family is unknown. One explanation is that there are modifier genes that affect the phenotype. These cases highlight the possibility of considering pathogenic variants in the GARS gene as a potential cause of early onset axonal polyneuropathy with atypical presentation.

GARS‐related disease in infantile spinal muscular atrophy: Implications for diagnosis and treatment

“…GARS has been associated with CMT2D and dSMA. Consistent with recent reports (Chung et al, ; Eskuri et al, ; James et al, ; Liao et al, ), our results suggest that GARS variants could potentially lead to early onset SMA‐like features depending on the nature and location of the amino acid change. Functional studies have shown that GARS consists of multiple domains including the catalytic, anti‐codon binding and dimerization domain, and mutations in each of these domains (Antonellis et al, ; Griffin et al, ) leads to axonal neuropathy.…”

“…Among the patients with dSMA, CMT2D, or infantile SMA and GARS variants published in the literature ( n = 45), we found that seven had infantile onset of symptoms (15.5%, age of onset less than 2 years old, Figure a,b). The majority of patients are diagnosed with dSMA or CMT2D, particularly when the variants are not in the anticodon‐binding or catalytic domain (Chung et al, ; Eskuri et al, ; James et al, ; Liao et al, ) (Figure b). Our identification of three patients with early‐onset SMA adds to the growing appreciation of the broad spectrum of dominant phenotypes associated with GARS pathogenic variants.…”

Mutation Analysis of GARS and Genotype-Phenotype Correlation in CMT2D/HMN5A in Chinese Patients

“…Most patients were of adolescent onset, while infant onset was also reported and tended to be more severe [14][15][16]. Severity of phenotype could be varying even in one family [14,16].…”

Infantile‐onset CMT2D/dSMA‐V in a Chinese family with parental germline mosaicism for a novel mutation in the GARS1 gene

“…CMT2D/dSMA-V typically presents with progressive muscle weakness and atrophy with adolescent or early adult onset (Antonellis et al, 2003); however, a few infantile or early childhood onset cases have been reported (Chae et al, 2015;Chung et al, 2018;Eskuri et al, 2012;James et al, 2006;Liao et al, 2015;Markovitz et al, 2020). Here we report, for the first time, a Chinese family with infantile onset of CMT2D/dSMA-V caused by GARS1 mutation (c.997G>C; NM_002047) probably inherited from mosaic parental germline mutation.…”