An atypical form of AOA2 with myoclonus associated with mutations in SETX and AFG3L2.
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.
Department of Medical Sciences, University of Torino, via Santena 19, 10126, Torino, Italy. cecilia.mancini@unito.it.
Cecilia
C
Mancini
Struttura Complessa Neurologia I, Department of Neuroscience and Mental Health, Città della Salute e della Scienza University Hospital, Torino, 10126, Italy. lorsi@cittadellasalute.to.it.
Laura
L
Orsi
Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. guoy@email.chop.edu.
Yiran
Y
Guo
BGI-Shenzhen, Shenzhen, 510803, China. lijiankang@genomics.cn.
Jiankang
J
Li
BGI-Shenzhen, Shenzhen, 510803, China. shenyulan@genomics.cn.
Yulan
Y
Chen
Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. wangf@email.chop.edu.
Fengxiang
F
Wang
Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. tianl@email.chop.edu.
Lifeng
L
Tian
BGI-Shenzhen, Shenzhen, 510803, China. liuxuanzhu@genomics.cn.
Xuanzhu
X
Liu
BGI-Shenzhen, Shenzhen, 510803, China. zhangjg@genomics.cn.
Jianguo
J
Zhang
BGI-Shenzhen, Shenzhen, 510803, China. jianghui@genomics.cn.|Shenzhen Key Laboratory of Genomics, Shenzhen, 518083, China. jianghui@genomics.cn.|The Guangdong Enterprise Key Laboratory of Human Disease Genomics, BGI-Shenzhen, Shenzhen, 510803, China. jianghui@genomics.cn.
Hui
H
Jiang
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15261, USA. bcn6@pitt.edu.
Bruce Shike
BS
Nmezi
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. t.tatsuta@uni-koeln.de.
Takashi
T
Tatsuta
Department of Medical Sciences, University of Torino, via Santena 19, 10126, Torino, Italy. elisa.giorgio84@libero.it.
Elisa
E
Giorgio
Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Torino, 10126, Italy. eleonora.digregorio@unito.it.
Eleonora
E
Di Gregorio
Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Torino, 10126, Italy. scavalieri@gmail.com.
Simona
S
Cavalieri
Department of Medical Sciences, University of Torino, via Santena 19, 10126, Torino, Italy. elisa.pozzi@unito.it.
Elisa
E
Pozzi
Struttura Complessa Neurologia I, Department of Neuroscience and Mental Health, Città della Salute e della Scienza University Hospital, Torino, 10126, Italy. paolo.mortara@unito.it.|Department of Neuroscience, University of Torino, Torino, 10126, Italy. paolo.mortara@unito.it.
Paolo
P
Mortara
Department of Neuroscience, University of Torino, Torino, 10126, Italy. marcella.caglio@unito.it.|Division of Neurology III, Department of Neuroscience and Mental Health, Città della Salute e della Scienza University Hospital, Torino, 10126, Italy. marcella.caglio@unito.it.
Maria Marcella
MM
Caglio
Department of Neuroscience, University of Torino, Torino, 10126, Italy. alessandro.balducci@unito.it.|Division of Neurology III, Department of Neuroscience and Mental Health, Città della Salute e della Scienza University Hospital, Torino, 10126, Italy. alessandro.balducci@unito.it.
Alessandro
A
Balducci
Struttura Complessa Neurologia I, Department of Neuroscience and Mental Health, Città della Salute e della Scienza University Hospital, Torino, 10126, Italy. lorenzo.pinessi@unito.it.|Department of Neuroscience, University of Torino, Torino, 10126, Italy. lorenzo.pinessi@unito.it.
Lorenzo
L
Pinessi
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. thomas.langer@uni-koeln.de.|Max-Planck-Institute for Biology of Aging, Cologne, 50931, Germany. thomas.langer@uni-koeln.de.
Thomas
T
Langer
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15261, USA. qpadiath@pitt.edu.
Quasar S
QS
Padiath
Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. hakonarson@email.chop.edu.|Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. hakonarson@email.chop.edu.|Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. hakonarson@email.chop.edu.
Hakon
H
Hakonarson
BGI-Shenzhen, Shenzhen, 510803, China. zhangxq@genomics.cn.|Shenzhen Key Laboratory of Genomics, Shenzhen, 518083, China. zhangxq@genomics.cn.|The Guangdong Enterprise Key Laboratory of Human Disease Genomics, BGI-Shenzhen, Shenzhen, 510803, China. zhangxq@genomics.cn.
Xiuqing
X
Zhang
Department of Medical Sciences, University of Torino, via Santena 19, 10126, Torino, Italy. alfredo.brusco@unito.it.|Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Torino, 10126, Italy. alfredo.brusco@unito.it.
Alfredo
A
Brusco
D049069:ATP-Dependent Proteases / Q000737:chemistry / Q000235:genetics*; D000074183:ATPases Associated with Diverse Cellular Activities; D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D002648:Child; D004265:DNA Helicases; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics; D005260:Female; D006720:Homozygote; D006801:Humans; D008969:Molecular Sequence Data; D064251:Multifunctional Enzymes; D009154:Mutation; D009207:Myoclonus / Q000150:complications*; D010375:Pedigree; D011187:Posture; D020365:RNA Helicases / Q000235:genetics*; D013132:Spinocerebellar Degenerations / Q000150:complications* / Q000235:genetics* / Q000503:physiopathology; D055815:Young Adult
D064251:Multifunctional Enzymes; D049069:ATP-Dependent Proteases; C120699:AFG3L2 protein, human; C484368:SETX protein, human; D000074183:ATPases Associated with Diverse Cellular Activities; D004265:DNA Helicases; D020365:RNA Helicases