title: Exome sequencing in undiagnosed inherited and sporadic ataxias.
abstract: Inherited ataxias are clinically and genetically heterogeneous, and a molecular diagnosis is not possible in most patients. Having excluded common sporadic, inherited and metabolic causes, we used an unbiased whole exome sequencing approach in 35 affected individuals, from 22 randomly selected families of white European descent. We defined the likely molecular diagnosis in 14 of 22 families (64%). This revealed de novo dominant mutations, validated disease genes previously described in isolated families, and broadened the clinical phenotype of known disease genes. The diagnostic yield was the same in both young and older-onset patients, including sporadic cases. We have demonstrated the impact of exome sequencing in a group of patients notoriously difficult to diagnose genetically. This has important implications for genetic counselling and diagnostic service provision.
authors.affiliation: 1 Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Pyle
authors.affiliation: 1 Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK.
authors.forename: Tania
authors.initials: T
authors.lastname: Smertenko
authors.affiliation: 1 Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK.
authors.forename: David
authors.initials: D
authors.lastname: Bargiela
authors.affiliation: 1 Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Griffin
authors.affiliation: 1 Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Duff
authors.affiliation: 2 Department of Clinical Biochemistry, Royal Victoria Infirmary, Newcastle upon Tyne Foundation Hospitals NHS Trust, Newcastle upon Tyne, NE1 4LP, UK.
authors.forename: Marie
authors.initials: M
authors.lastname: Appleton
authors.affiliation: 1 Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Douroudis
authors.affiliation: 1 Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK.
authors.forename: Gerald
authors.initials: G
authors.lastname: Pfeffer
authors.affiliation: 1 Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK.
authors.forename: Mauro
authors.initials: M
authors.lastname: Santibanez-Koref
authors.affiliation: 1 Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK.
authors.forename: Gail
authors.initials: G
authors.lastname: Eglon
authors.affiliation: 1 Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK.
authors.forename: Patrick
authors.initials: P
authors.lastname: Yu-Wai-Man
authors.affiliation: 3 Department of Paediatric Neurology, Royal Victoria Infirmary, Newcastle upon Tyne Foundation Hospitals NHS Trust, Newcastle upon Tyne, NE1 4LP, UK.
authors.forename: Venkateswaran
authors.initials: V
authors.lastname: Ramesh
authors.affiliation: 1 Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK.
authors.forename: Rita
authors.initials: R
authors.lastname: Horvath
authors.affiliation: 1 Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK patrick.chinnery@ncl.ac.uk.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D019295:Computational Biology; D059472:Exome / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009460:Neurologic Examination; D017422:Sequence Analysis, DNA; D013132:Spinocerebellar Degenerations / Q000235:genetics*; D044465:White People; D055815:Young Adult
keywords: ataxia; whole exome sequencing