title: Infantile onset spinocerebellar ataxia caused by compound heterozygosity for Twinkle mutations and modeling of Twinkle mutations causing recessive disease.
abstract: Mutations in nuclear genes required for the replication and maintenance of mitochondrial DNA cause progressive multisystemic neuromuscular disorders with overlapping phenotypes. Biallelic mutations in C10orf2, encoding the Twinkle mitochondrial DNA helicase, lead to infantile-onset cerebellar ataxia (IOSCA), as well as milder and more severe phenotypes. We present a 13-year-old girl with ataxia, severe hearing loss, optic atrophy, peripheral neuropathy, and hypergonadotropic hypogonadism. Whole-exome sequencing revealed that the patient is compound heterozygous for previously unreported variants in the C10orf2 gene: a paternally inherited frameshift variant (c.333delT; p.L112Sfs*3) and a maternally inherited missense variant (c.904C>T; p.R302W). The identification of novel C10orf2 mutations extends the spectrum of mutations in the Twinkle helicase causing recessive disease, in particular the intermediate IOSCA phenotype. Structural modeling suggests that the p.R302W mutation and many other recessively inherited Twinkle mutations impact the position or interactions of the linker region, which is critical for the oligomeric ring structure and activity of the helicase. This study emphasizes the utility of whole-exome sequencing for the genetic diagnosis of a complex multisystemic disorder.
authors.affiliation: Department of Medicine (Medical Genetics), University of Washington, Seattle, Washington 98195, USA;
authors.forename: Sarah B
authors.identifier: 0000-0001-6739-7135
authors.initials: SB
authors.lastname: Pierce
authors.affiliation: Department of Medicine (Medical Genetics), University of Washington, Seattle, Washington 98195, USA;
authors.forename: Suleyman
authors.initials: S
authors.lastname: Gulsuner
authors.affiliation: Greenwood Genetic Center, Greenville, South Carolina 29605, USA;
authors.forename: Gail A
authors.initials: GA
authors.lastname: Stapleton
authors.affiliation: Department of Medicine (Medical Genetics), University of Washington, Seattle, Washington 98195, USA;
authors.forename: Tom
authors.initials: T
authors.lastname: Walsh
authors.affiliation: Department of Medicine (Medical Genetics), University of Washington, Seattle, Washington 98195, USA;
authors.forename: Ming K
authors.initials: MK
authors.lastname: Lee
authors.affiliation: Department of Medicine (Medical Genetics), University of Washington, Seattle, Washington 98195, USA;
authors.forename: Jessica B
authors.initials: JB
authors.lastname: Mandell
authors.affiliation: Pediatric Neurology, Greenville Health System, Greenville, South Carolina 29615, USA;
authors.forename: Augusto
authors.initials: A
authors.lastname: Morales
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA;
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Klevit
authors.affiliation: Department of Medicine (Medical Genetics), University of Washington, Seattle, Washington 98195, USA;; Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Mary-Claire
authors.initials: MC
authors.lastname: King
authors.affiliation: Greenwood Genetic Center, Greenville, South Carolina 29605, USA;
authors.forename: R Curtis
authors.initials: RC
authors.lastname: Rogers
keywords: bilateral sensorineural hearing impairment; decreased distal sensory nerve action potential; gait ataxia; hypergonadotropic hypogonadism; impaired distal proprioception; impaired vibration sensation at ankles; infantile spasms; progressive external ophthalmoplegia; sensorimotor neuropathy