Genetic and Clinical Features in 24 Chinese Distal Hereditary Motor Neuropathy Families

Abstract

Background and Objectives: Distal hereditary motor neuropathy (dHMN) is a clinically and genetically heterogeneous group of inherited neuropathies. The objectives of this study were to report the clinical and genetic features of dHMN patients in a Chinese cohort. Aims and Methods: We performed clinical assessments and whole-exome sequencing in 24 dHMN families from Mainland China. We conducted a retrospective analysis of the data and investigated the frequency and clinical features of patients with a confirmed mutation. Results: Two novel heterozygous mutations in GARS, c.373G>C (p.E125Q) and c.1015G>A (p.G339R), were identified and corresponded to the typical dHMN-V phenotype. Together with families with WARS, SORD, SIGMAR1, and HSPB1 mutations, 29.2% of families (7/24) acquired a definite genetic diagnosis. One novel heterozygous variant of uncertain significance, c.1834G>A (p.G612S) in LRSAM1, was identified in a patient with mild dHMN phenotype. Conclusion: Our study expanded the mutation spectrum of GARS mutations and added evidence that GARS mutations are associated with both axonal Charcot-Marie-Tooth and dHMN phenotypes. Mutations in genes encoding aminoamide tRNA synthetase (ARS) might be a frequent cause of autosomal dominant-dHMN, and SORD mutation might account for a majority of autosomal recessive-dHMN cases. The relatively low genetic diagnosis yield indicated more causative dHMN genes need to be discovered.

Keywords: GARS; SORD; clinical features; distal hereditary motor neuropathy; genetic diagnosis; genetic distribution.

Figure 1

Pedigree, sequencing electropherograms, conservation analysis, and clinical imaging features of distal hereditary motor neuropathy (dHMN) families with GARS mutation. (A) Pedigrees of family1 (GARS c. 373G>C) and family 2 (GARS c.1015G>A), and chromatograms of the mutation sites confirmed by Sanger sequencing. The GARS c.1015G>A variant is shown to be a de novo variant by comparing 22 core STR markers. Square, male; Circle, female; Black filled symbol, clinically and electromyogram confirmed affected individual; Empty symbol, clinically healthy individual; M, mutant type; W, wild-type; Arrows, probands. (B) Conservation of the residues surrounding Glu acid (E) 125 (red) and Gly (G) 339 in GARS among species. (C) Images of the upper and lower limbs of the proband in family 2(II-1).

Figure 2

Genotype distribution and age of onset distribution in Chinese dHMN families. (A) Of the 24 dHMN families, the diagnosis was genetically confirmed in seven and a total of six genotypes have been identified. (B) Of the total 33 dHMN patients in 24 families, 75.8% (25/33) reported disease onset in the first two decades.

Figure 3

Schematic representation of GARS gene/protein and location of mutations. (A) Distribution CMT2D/dHMN-associated mutations in the three domains of the cytosolic human glycyl-tRNA synthetase (GlyRS). Red: Novel mutations identified with dHMN-V in this study. Most reported GARS mutations are located in the catalytic domain or lie in one of the eight opened surface regions. Amino acid nomenclature based on transcript NM 002047.2(739 a.a). (B) Molecular structures of integral type (left), wild type (middle), and mutant type (right) of human GlyRS (PDB ID: 4KR2). Both residues, p.E125 and p.G339, are strictly conserved in opened-up surface area of hGlyRS, among which p.G339 also located within the glycine-binding pocket. The substitution of p.E125Q altered the charge and space resistance with adjacent amino acids. The substitution of p.G339R engendered neomorphic hydrogen bonding interactions between residue p.G339 and p.Y148/p.E125.