An atypical form of AOA2 with myoclonus associated with mutations in SETX and AFG3L2

BMC Medical Genetics

Alfredo Brusco⁹  Xiuqing Zhang²  Hakon Hakonarson⁷  Quasar S Padiath⁶  Thomas Langer⁵  Lorenzo Pinessi³  Alessandro Balducci⁸  Maria Marcella Caglio⁸  Paolo Mortara³  Elisa Pozzi⁴  Simona Cavalieri⁹  Eleonora Di Gregorio⁹  Elisa Giorgio⁴  Takashi Tatsuta⁵  Bruce Shike Nmezi⁶  Hui Jiang²  Jianguo Zhang¹  Xuanzhu Liu¹  Lifeng Tian⁷  Fengxiang Wang⁷  Yulan Chen¹  Jiankang Li¹  Yiran Guo⁷  Laura Orsi³  Cecilia Mancini⁴ 

[1] BGI-Shenzhen, Shenzhen 510803, China;The Guangdong Enterprise Key Laboratory of Human Disease Genomics, BGI-Shenzhen, Shenzhen 510803, China;Struttura Complessa Neurologia I, Department of Neuroscience and Mental Health, Città della Salute e della Scienza University Hospital, Torino 10126, Italy;Department of Medical Sciences, University of Torino, via Santena 19, Torino, 10126, Italy;Institute for Genetics, Center for Molecular Medicine (CMMC), Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne 50931, Germany;Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh 15261, PA, USA;Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia 19104, PA, USA;Division of Neurology III, Department of Neuroscience and Mental Health, Città della Salute e della Scienza University Hospital, Torino 10126, Italy;Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Torino 10126, Italy

关键词: Myoclonus;    Autosomal recessive ataxia;    Ataxia with Oculomotor Apraxia Type 2;    SCAR1;    Modifier genes;    SETX;    Senataxin;    Exome sequencing;    AFG3L2;   

Others  :  1177689
DOI  :  10.1186/s12881-015-0159-0

 received in 2014-11-19, accepted in 2015-02-26,  发布年份 2015

【 摘 要 】

Background

Hereditary ataxias are a heterogeneous group of neurodegenerative disorders, where exome sequencing may become an important diagnostic tool to solve clinically or genetically complex cases.

Methods

We describe an Italian family in which three sisters were affected by ataxia with postural/intentional myoclonus and involuntary movements at onset, which persisted during the disease. Oculomotor apraxia was absent. Clinical and genetic data did not allow us to exclude autosomal dominant or recessive inheritance and suggest a disease gene.

Results

Exome sequencing identified a homozygous c.6292C > T (p.Arg2098*) mutation in SETX and a heterozygous c.346G > A (p.Gly116Arg) mutation in AFG3L2 shared by all three affected individuals. A fourth sister (II.7) had subclinical myoclonic jerks at proximal upper limbs and perioral district, confirmed by electrophysiology, and carried the p.Gly116Arg change. Three siblings were healthy.

Pathogenicity prediction and a yeast-functional assay suggested p.Gly116Arg impaired m-AAA (ATPases associated with various cellular activities) complex function.

Conclusions

Exome sequencing is a powerful tool in identifying disease genes. We identified an atypical form of Ataxia with Oculoapraxia type 2 (AOA2) with myoclonus at onset associated with the c.6292C > T (p.Arg2098*) homozygous mutation. Because the same genotype was described in six cases from a Tunisian family with a typical AOA2 without myoclonus, we speculate this latter feature is associated with a second mutated gene, namely AFG3L2 (p.Gly116Arg variant).

We suggest that variant phenotypes may be due to the combined effect of different mutated genes associated to ataxia or related disorders, that will become more apparent as the costs of exome sequencing progressively will reduce, amplifying its diagnostics use, and meanwhile proposing significant challenges in the interpretation of the data.

【 授权许可】

   
2015 Mancini et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

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