Mancini, Cecilia ORCID: 0000-0003-1282-0404, Orsi, Laura, Guo, Yiran, Li, Jiankang, Chen, Yulan, Wang, Fengxiang, Tian, Lifeng, Liu, Xuanzhu, Zhang, Jianguo, Jiang, Hui, Nmezi, Bruce Shike, Tatsuta, Takashi, Giorgio, Elisa ORCID: 0000-0003-4076-4649, Di Gregorio, Eleonora, Cavalieri, Simona, Pozzi, Elisa, Mortara, Paolo, Caglio, Maria Marcella, Balducci, Alessandro, Pinessi, Lorenzo, Langer, Thomas ORCID: 0000-0003-1250-1462, Padiath, Quasar S., Hakonarson, Hakon, Zhang, Xiuqing and Brusco, Alfredo ORCID: 0000-0002-8318-7231 (2015). An atypical form of AOA2 with myoclonus associated with mutations in SETX and AFG3L2. BMC Med. Genet., 16. LONDON: BIOMED CENTRAL LTD. ISSN 1471-2350

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Abstract

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 (11.7) 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Mancini, CeciliaUNSPECIFIEDorcid.org/0000-0003-1282-0404UNSPECIFIED
Orsi, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guo, YiranUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, JiankangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chen, YulanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, FengxiangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tian, LifengUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liu, XuanzhuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhang, JianguoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jiang, HuiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nmezi, Bruce ShikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tatsuta, TakashiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Giorgio, ElisaUNSPECIFIEDorcid.org/0000-0003-4076-4649UNSPECIFIED
Di Gregorio, EleonoraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cavalieri, SimonaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pozzi, ElisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mortara, PaoloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Caglio, Maria MarcellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Balducci, AlessandroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pinessi, LorenzoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Langer, ThomasUNSPECIFIEDorcid.org/0000-0003-1250-1462UNSPECIFIED
Padiath, Quasar S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hakonarson, HakonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhang, XiuqingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brusco, AlfredoUNSPECIFIEDorcid.org/0000-0002-8318-7231UNSPECIFIED
URN: urn:nbn:de:hbz:38-404848
DOI: 10.1186/s12881-015-0159-0
Journal or Publication Title: BMC Med. Genet.
Volume: 16
Date: 2015
Publisher: BIOMED CENTRAL LTD
Place of Publication: LONDON
ISSN: 1471-2350
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
OCULOMOTOR APRAXIA TYPE-2; CEREBELLAR ATAXIAS; MITOCHONDRIA; ONSET; SCA28Multiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/40484

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