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. 2017 Nov 14;11(1):28.
doi: 10.1186/s40246-017-0124-4.

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

Abdulaziz Alsemari  1   2 , Banan Al-Younes  3   2 , Ewa Goljan  3   2 , Dyala Jaroudi  3   2 , Faisal BinHumaid  3   2 , Brian F Meyer  3   2 , Stefan T Arold  4 , Dorota Monies  5   6
Affiliations

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

Abdulaziz Alsemari et al. Hum Genomics. .

Erratum in

Abstract

Background: Most 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.

Results: A 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.

Conclusions: These 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.

Keywords: Angelman; Dysmorphism; Hypogonadism; Mitochondrial; Syndromic; Vitamin D deficiency.

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Conflict of interest statement

Ethics approval and consent to participate

Written informed consent was obtained from all enrolled participants in an IRB-approved project (RAC 2140029). The study was carried out in accordance with the declaration of Helsinki under IRB guidelines of the King FaisalSpecialist Hospital and Research Centre (KFSHRC), Riyadh, Saudi Arabia.

Consent for publication

Written informed consent was obtained to publish the video included in the supplement.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Identification of disease locus on chromosome 6: a Pedigree of extended family with a novel syndromic disorder. b Genome-wide linkage analysis revealed a peak with a maximum LOD score of 4.11 on chromosome 6. c AutoSNPa output for chromosome 6 reveals an ROH (boxed in red) shared among affected members (V:2, V:3, V:4, and V:8) and not present in unaffected individuals or parents. Output for chromosome 18 excludes this locus because the ROH is not shared with affected individual V:10
Fig. 2
Fig. 2
Clinical features: a Apparent happy demeanor with easily excitable personality. b Microcephaly, prognathia, and wide spaced teeth. c There are usually flexed arm positions particularly during movement. d Short stature and increasingly chair bound
Fig. 3
Fig. 3
VARS2 mutation: a Filtering strategy used for identification of a causative mutation. b DNA electrophoregram with the G>A change in VARS2 (NM_006295:exon29:c.G3650A:p.R1217H)
Fig. 4
Fig. 4
Computational structural analysis of mutant: Homology model of the VARS2 tRNA synthetase domain, based on the PDB id 1gax (36% sequence id, RaptorX p value 1.12e-19). a The C-terminal coiled-coild domain is shown in cyan. R1217 is highlighted with carbon atoms shown in green. tRNA is shown with orange backbone. b Inlay: Zoom of the indicated region. H1217 is shown with gray carbon atoms. The tRNA D loop is shown with carbon atoms in magenta
See this image and copyright information in PMC

References

    1. Al-Mujadi H, AR AR, Katzarov MG, Dehrab NA, Batra YK, Al-Qattan AR. Preemptive gabapentin reduces postoperative pain and opioid demand following thyroid surgery. Can J Anaesth. 2006;53:268–273. doi: 10.1007/BF03022214. - DOI - PubMed
    1. Fernell E. Aetiological factors and prevalence of severe mental retardation in children in a Swedish municipality: the possible role of consanguinity. Dev Med Child Neurol. 1998;40:608–611. doi: 10.1111/j.1469-8749.1998.tb15426.x. - DOI - PubMed
    1. Ropers HH. Genetics of early onset cognitive impairment. Annu Rev Genomics Hum Genet. 2010;11:161–187. doi: 10.1146/annurev-genom-082509-141640. - DOI - PubMed
    1. de Ligt J, Willemsen MH, van Bon BW, Kleefstra T, Yntema HG, Kroes T, Vulto-van Silfhout AT, Koolen DA, de Vries P, Gilissen C, et al. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med. 2012;367:1921–1929. doi: 10.1056/NEJMoa1206524. - DOI - PubMed
    1. Fryns JP, de Ravel TJ. London Dysmorphology Database, London Neurogenetics Database and Dysmorphology Photo Library on CD-ROM [Version 3] 2001R. M. Winter, M. Baraitser, Oxford University Press, ISBN 019851-780, pound sterling 1595. Hum Genet. 2002;111:113. doi: 10.1007/s00439-002-0759-6. - DOI

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