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Recessive VARS2 Mutation Underlies a Novel Syndrome with Epilepsy, Mental Retardation, Short Stature, Growth Hormone Deficiency

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Recessive VARS2 Mutation Underlies a Novel Syndrome with Epilepsy, Mental Retardation, Short Stature, Growth Hormone Deficiency Alsemari et al. Human Genomics (2017) 11:28 DOI 10.1186/s40246-017-0124-4 PRIMARY RESEARCH Open Access Recessive VARS2 mutation underlies a novel syndrome with epilepsy, mental retardation, short stature, growth hormone deficiency, and hypogonadism Abdulaziz Alsemari1,3, Banan Al-Younes2,3, Ewa Goljan2,3, Dyala Jaroudi2,3, Faisal BinHumaid2,3, Brian F. Meyer2,3, Stefan T. Arold4 and Dorota Monies2,3* 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: Syndromic, Angelman, Mitochondrial, Dysmorphism, Hypogonadism, Vitamin D deficiency Background A number of single-gene disorders result in mental re- Mental retardation (MR) affects approximately 1–3% of tardation. Many of these are associated with atypical or the human population. Both genetic and environmental dysmorphic physical characteristics. Such conditions in- factors are responsible for causing MR, but in almost clude fragile X syndrome, neurofibromatosis, tuberous 60% of the cases, the actual cause cannot be identified sclerosis, Noonan’s syndrome, Cornelia de Lange’s syn- precisely [1, 2]. In developed countries, most severe drome, and Angelman syndrome(AS) [5]. AS is usually forms of intellectual disability are thought to have a gen- considered as a diagnosis in individuals with severe de- etic cause [3]. Mutations in more than 400 genes have velopmental delay, in combination with seizures, ataxia, been linked to intellectual disability, but most of these hypermotoric behaviors, and absence of speech. Ninety mutations have a very low prevalence and their pheno- percent of these individuals have an identifiable molecu- types are often indistinguishable [4]. lar defect that results in the loss of expression of mater- nally inherited UBE3A (encoding E6AP) in the brain [6]. Over the last few years, many novel syndromes that * Correspondence: [email protected] mimic AS have been delineated and it is now recognized 2 Department of Genetics, King Faisal Specialist Hospital and Research Centre, that some individuals who were clinically diagnosed with MBC 03, PO Box 3354, Riyadh 11211, Saudi Arabia “ ” 3Saudi Human Genome Project, King Abdulaziz City for Science and test-negative AS have one of these AS-like syndromes Technology, Riyadh, Saudi Arabia instead. Their phenotypes include severe intellectual Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Alsemari et al. Human Genomics (2017) 11:28 Page 2 of 7 disability, motor delay, variable degrees of speech delay sequence was generated per sequencing run. Reads were ranging from being completely non-verbal to being able mapped to UCSC hg19 (http://genome.ucsc.edu/) and to speak in short sentences, autistic and maladaptive be- variants identified using the Ion Torrent pipeline (Life haviors, short attention span, and seizures [7]. Technologies, Carlsbad, CA, USA). The resultant variant We report a novel autosomal recessive syndromic dis- caller file (vcf) was filtered to include only homozygous order with clinical resemblance to AS. The clinical variants within the pre-determined ROH (shared by af- spectrum includes severe mental retardation, ataxia, fecteds only) that were absent from dbSNP, 1000 ge- speech impairment, epilepsy, short stature, microceph- nomes, approximately 2000 Saudi exomes. Included aly, flap occiput, protruding tongue, prognathia, tremu- variants were further selected based upon pathogenicity lous movement of limbs, apparent happy demeanor, predicted by Polyphen2 (http://genetics.bwh.harvar- easily excitable personality, and excessive chewing d.edu/pph2/) and SIFT (http://sift.jcvi.org/). Potential mouth behaviors. In addition, there were severe growth causative variants were confirmed by Sanger sequencing hormone deficiency, hypogonadism, and severe osteo- and screened further for familial segregation based upon malacia. Whole exome sequencing of the affected pa- autosomal recessive inheritance. For confirmation, an tients identified a homozygous mutation in VARS2. amplicon incorporating the candidate variant was ampli- fied and sequenced using a BigDye Terminator kit (Ap- Methods plied Biosystems, Foster City, CA) and run on an ABI Subjects and nucleic acid extraction 3730xl automated sequencer (Applied Biosystems, Foster Four patients from a consanguineous extended family City, CA). SeqScape v.2.6 software (Applied Biosystems, from the same region of Saudi Arabia were examined by Foster City, CA) was used to align sequence data and a neurologist (AAS), in the department of Neurosci- identify variants. ences, King Faisal Specialist Hospital and Research Center (KFSHRC). They were diagnosed with an Computational structural analysis of mutants Angelman-like syndrome. All subjects were enrolled Sequences were retrieved from the Uniprot database. under a KFSHRC IRB-approved (RAC# 13-MED2056- BLAST and SwissModel [8] were used to search for suit- 20) protocol with full-written informed consent. Gen- able structural templates in the Protein Data Bank omic DNA was extracted from peripheral blood samples (PDB). SwissModel, RaptorX [9], and I-Tasser [10] were using standard procedures (Flexi Gene DNA Handbook, used to produce homology models. Models were manu- Qiagen). Samples were quantitated spectrophotometric- ally inspected, and mutations evaluated, using the Pymol ally and stored at − 20 °C. program (pymol.org). Disorder and secondary structure elements were predicted using RaptorX. Transmem- Linkage and homozygosity mapping brane helices were predicted using Phobius [11]. Func- All participating individuals (affected and unaffected) tional information was compiled from various resources, were genotyped using an Affymetrix Axiom array (Affy- including Uniprot [12], InterPro [13], and publications metrix, Santa Clara, CA, USA) following the manufac- associated with the model templates used. turer’s protocol (http://www.affymetrix.com/support/ technical/manuals.affx). Resulting genotypes were ana- Results lyzed for shared runs of homozygosity (ROH) using Clinical profile autoSNPa (http://dna.leeds.ac.uk/autosnpa/). Linkage The index case (V:3) (Fig. 1a), a 23-year-old male was analysis was performed using the Allegro module of Easy a product of full-term pregnancy and normal delivery. Linkage assuming autosomal recessive inheritance and He was well until the age of 4 months when he 100% penetrance (http://genetik.charite.de/hoffmann/ started to have generalized tonic clonic seizures. At easyLINKAGE/index.html). the age of 1 year, the family noticed that the patient had delayed development. He had delayed sitting, de- Whole exome sequencing and analysis layed standing, and only started to crawl at the age of DNA was amplified to obtain a whole exome Ion Proton 2 years. The patient eventually exhibited severe devel- AmpliSeq library which was further used for emulsion opmental delay and severe speech impairment. The PCR on an Ion OneTouch System followed by an en- speech impairment was more receptive than expres- richment process using an Ion OneTouch ES, both pro- sive. Upon reviewing his family history, there were cedures following the manufacturer’s instructions (Life three other similarly affected siblings (one brother Technologies, Carlsbad, CA, USA). The template- and two sisters). He also has four similarly affected positive Ion PI Ion Sphere particles were processed for cousins (two males and two females) (Fig. 1a). sequencing on the Ion Proton sequencer (Life Technolo- Affected individuals usually have incoordination of move- gies, Carlsbad, CA, USA). Approximately 15–17 Gb of ment until adolescence at which point they stop walking, Alsemari et al. Human Genomics (2017) 11:28 Page 3 of 7 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
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