Dataset Information

Identification of a novel mutation in the APTX gene associated with ataxia-oculomotor apraxia.

ABSTRACT: Hereditary ataxias are a clinically and genetically heterogeneous family of disorders defined by the inability to control gait and muscle coordination. Given the nonspecific symptoms of many hereditary ataxias, precise diagnosis relies on molecular genetic testing. To this end, we conducted whole-exome sequencing (WES) on a large consanguineous Iranian family with hereditary ataxia and oculomotor apraxia. WES in five affected and six unaffected individuals resulted in the identification of a homozygous novel stop-gain mutation in the APTX gene (c.739A>T; p.Lys247*) that segregates with the phenotype. Mutations in the APTX (OMIM 606350) gene are associated with ataxia with oculomotor apraxia type 1 (OMIM 208920).

SUBMITTER: Inlora J

PROVIDER: S-EPMC5701303 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Identification of a novel mutation in the <i>APTX</i> gene associated with ataxia-oculomotor apraxia.

Inlora Jingga J Sailani M Reza MR Khodadadi Hamidreza H Teymurinezhad Ahmad A Takahashi Shinichi S Bernstein Jonathan A JA Garshasbi Masoud M Snyder Michael P MP

Cold Spring Harbor molecular case studies 20171121 6

Hereditary ataxias are a clinically and genetically heterogeneous family of disorders defined by the inability to control gait and muscle coordination. Given the nonspecific symptoms of many hereditary ataxias, precise diagnosis relies on molecular genetic testing. To this end, we conducted whole-exome sequencing (WES) on a large consanguineous Iranian family with hereditary ataxia and oculomotor apraxia. WES in five affected and six unaffected individuals resulted in the identification of a hom ...[more]

PMID: 28652255

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Project description:ObjectivesAutosomal recessive inherited ataxia with oculomotor apraxia type 2 (AOA2), caused by SETX gene mutations, is characterized by early-onset, progressive cerebellar ataxia, peripheral neuropathy, oculomotor apraxia and elevated serum α-fetoprotein (AFP). This study aimed to expand and summarize the clinical and genetic characteristics of SETX variants related to AOA2.MethodsThe biochemical parameters, electromyogram and radiological findings of the patient were evaluated. Whole-exome sequencing (WES) was performed on the patient using next-generation sequencing (NGS), the variants were confirmed by Sanger sequencing and the pathogenicity of the variants was classified according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines. We reviewed 57 studies of AOA2 patients with SETX mutations and collected clinical and genetic information.ResultsThe patient was a 40-year-old Chinese woman who primarily presented with numbness and weakness of the lower limbs in her teenage years. She had elevated AFP, increased serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and decreased anti-Müllerian hormone (AMH) levels. We identified a novel homozygous missense mutation of the SETX gene, c.7118 C>T (p. Thr2373Ile), in the patient via Whole-exome and Sanger sequencing. The variant was located in the DNA/RNA helicase domain and is highly conserved. The protein prediction analysis verified the SETX variant as a damaging alteration and ACMG/AMP guidelines classified it as likely pathogenic. Through a literature review, we identified 229 AOA2 cases with SETX variants, and among the variants, 156 SETX variants were exonic. We found that 107 (46.7%) patients were European, 50 (21.8%) were African and 48 (21.0%) were Asian. Among the Asian patients, five from two families were Mainland Chinese. The main clinical features were cerebellar ataxia (100%), peripheral neuropathy (94.6%), cerebellar atrophy (95.3%) and elevated AFP concentration (92.0%). Most reported SETX mutations in AOA2 patients were missense, frameshift and nonsense mutations.ConclusionWe discovered a novel homozygous variant of the SETX gene as a cause of AOA2 in the current patient and expanded the genotypic spectrum of AOA2. Moreover, the clinical features of AOA2 and genetic findings in SETX were assessed in reported cohorts and are summarized in the present study.

Dataset Information

Identification of a novel mutation in the APTX gene associated with ataxia-oculomotor apraxia.

Publications

Identification of a novel mutation in the <i>APTX</i> gene associated with ataxia-oculomotor apraxia.

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