title: Targeted high throughput sequencing in hereditary ataxia and spastic paraplegia.
abstract: Hereditary ataxia and spastic paraplegia are heterogeneous monogenic neurodegenerative disorders. To date, a large number of individuals with such disorders remain undiagnosed. Here, we have assessed molecular diagnosis by gene panel sequencing in 105 early and late-onset hereditary ataxia and spastic paraplegia probands, in whom extensive previous investigations had failed to identify the genetic cause of disease. Pathogenic and likely-pathogenic variants were identified in 20 probands (19%) and variants of uncertain significance in ten probands (10%). Together these accounted for 30 probands (29%) and involved 18 different genes. Among several interesting findings, dominantly inherited KIF1A variants, p.(Val8Met) and p.(Ile27Thr) segregated in two independent families, both presenting with a pure spastic paraplegia phenotype. Two homozygous missense variants, p.(Gly4230Ser) and p.(Leu4221Val) were found in SACS in one consanguineous family, presenting with spastic ataxia and isolated cerebellar atrophy. The average disease duration in probands with pathogenic and likely-pathogenic variants was 31 years, ranging from 4 to 51 years. In conclusion, this study confirmed and expanded the clinical phenotypes associated with known disease genes. The results demonstrate that gene panel sequencing and similar sequencing approaches can serve as efficient diagnostic tools for different heterogeneous disorders. Early use of such strategies may help to reduce both costs and time of the diagnostic process.
authors.affiliation: Department of Neurology, Oslo University Hospital, Oslo, Norway.
authors.forename: Zafar
authors.identifier: http://orcid.org/0000-0002-6387-8019
authors.initials: Z
authors.lastname: Iqbal
authors.affiliation: Department of Neurology, Oslo University Hospital, Oslo, Norway.|Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Siri L
authors.initials: SL
authors.lastname: Rydning
authors.affiliation: Department of Neurology, Oslo University Hospital, Oslo, Norway.|Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Iselin M
authors.initials: IM
authors.lastname: Wedding
authors.affiliation: Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.|Department of Neurology, Drammen Hospital, Vestre Viken Hospital Trust, Drammen, Norway.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Koht
authors.affiliation: Department of Neurology, Oslo University Hospital, Oslo, Norway.|Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Lasse
authors.initials: L
authors.lastname: Pihlstrøm
authors.affiliation: Department of Neurology, Oslo University Hospital, Oslo, Norway.
authors.forename: Aina H
authors.initials: AH
authors.lastname: Rengmark
authors.affiliation: Department of Neurology, Oslo University Hospital, Oslo, Norway.
authors.forename: Sandra P
authors.initials: SP
authors.lastname: Henriksen
authors.affiliation: Department of Neurology, Oslo University Hospital, Oslo, Norway.|Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Chantal M E
authors.initials: CM
authors.lastname: Tallaksen
authors.affiliation: Department of Neurology, Oslo University Hospital, Oslo, Norway.
authors.forename: Mathias
authors.initials: M
authors.lastname: Toft
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D005260:Female; D006360:Heat-Shock Proteins / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016547:Kinesins / Q000235:genetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D009128:Muscle Spasticity / Q000235:genetics; D010375:Pedigree; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics*; D020754:Spinocerebellar Ataxias / Q000151:congenital / Q000235:genetics; D013132:Spinocerebellar Degenerations / Q000235:genetics*; D055815:Young Adult
chemical_list: D006360:Heat-Shock Proteins; C094065:KIF1A protein, human; C404403:SACS protein, human; D016547:Kinesins