Recessive VARS2 mutation underlies a novel syndrome with epilepsy, mental retardation, short stature, growth hormone deficiency, and hypogonadism

Abdulaziz Alsemari,Ewa Goljan,Stefan T Arold,Dorota Monies,Brian F Meyer,Dyala Jaroudi,Banan Al-Younes,Faisal Binhumaid

doi:10.1186/s40246-017-0124-4

Abstract

BackgroundMost mitochondrial and cytoplasmic aminoacyl-tRNA synthetases (aaRSs) are encoded by nuclear genes. Syndromic disorders resulting from mutation of aaRSs genes display significant phenotypic heterogeneity. We expand aaRSs-related phenotypes through characterization of the clinical and molecular basis of a novel autosomal-recessive syndrome manifesting severe mental retardation, ataxia, speech impairment, epilepsy, short stature, microcephaly, hypogonadism, and growth hormone deficiency.ResultsA G>A variant in exon 29 of VARS2 (c.3650G>A) (NM_006295) was identified in the index case. This homozygous variant was confirmed by Sanger sequencing and segregated with disease in the family studied. The c.3650G>A change results in alteration of arginine to histidine at residue 1217 (R1217H) of the mature protein and is predicted to be pathogenic.ConclusionsThese findings contribute to a growing list of aaRSs disorders, broadens the spectrum of phenotypes attributable to VARS2 mutations, and provides new insight into genotype-phenotype correlations among the mitochondrial synthetase genes.

Highlights

Most mitochondrial and cytoplasmic aminoacyl-tRNA synthetases are encoded by nuclear genes
Subjects and nucleic acid extraction Four patients from a consanguineous extended family from the same region of Saudi Arabia were examined by a neurologist (AAS), in the department of Neurosciences, King Faisal Specialist Hospital and Research Center (KFSHRC)
The mRNA interacts with the ribosomal complex which reads the sequence of mRNA bases

Summary

Introduction

Most mitochondrial and cytoplasmic aminoacyl-tRNA synthetases (aaRSs) are encoded by nuclear genes. A number of single-gene disorders result in mental retardation Many of these are associated with atypical or dysmorphic physical characteristics. AS is usually considered as a diagnosis in individuals with severe developmental delay, in combination with seizures, ataxia, hypermotoric behaviors, and absence of speech. Ninety percent of these individuals have an identifiable molecular defect that results in the loss of expression of maternally inherited UBE3A (encoding E6AP) in the brain [6]. Over the last few years, many novel syndromes that mimic AS have been delineated and it is recognized that some individuals who were clinically diagnosed with “test-negative AS” have one of these AS-like syndromes instead

Methods

Results

Discussion

Conclusion