title: Exome sequencing is a useful diagnostic tool for complicated forms of hereditary spastic paraplegia.
abstract: Hereditary spastic paraplegias constitute a heterogeneous group of neurodegenerative diseases encompassing pure and complicated forms, for which at least 52 loci and 31 causative genes have been identified. Although mutations in the SPAST gene explain approximately 40% of the pure autosomal dominant forms, molecular diagnosis can be challenging for the sporadic and recessive forms, which are often complicated and clinically overlap with a broad number of movement disorders. The validity of exome sequencing as a routine diagnostic approach in the movement disorder clinic needs to be assessed. The main goal of this study was to explore the usefulness of an exome analysis for the diagnosis of a complicated form of spastic paraplegia. Whole-exome sequencing was performed in two Spanish siblings with a neurodegenerative syndrome including upper and lower motor neuron, ocular and cerebellar signs. Exome sequencing revealed that both patients carry a novel homozygous nonsense mutation in exon 15 of the SPG11 gene (c.2678G>A; p.W893X), which was not found in 584 Spanish control chromosomes. After many years of follow-up and multiple time-consuming genetic testing, we were able to diagnose these patients by making use of whole-exome sequencing, showing that this is a cost-efficient diagnostic tool for the movement disorder specialist.
authors: Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal; Center of Research in Natural Resources (CIRN) and Department of Biology, University of the Azores, Ponta Delgada, Portugal.
authors: C
authors: C
authors: Bettencourt
authors: J L
authors: JL
authors: López-Sendón
authors: J
authors: J
authors: García-Caldentey
authors: P
authors: P
authors: Rizzu
authors: I M C
authors: IM
authors: Bakker
authors: O
authors: O
authors: Shomroni
authors: B
authors: B
authors: Quintáns
authors: J R
authors: JR
authors: Dávila
authors: M R
authors: MR
authors: Bevova
authors: M-J
authors: MJ
authors: Sobrido
authors: P
authors: P
authors: Heutink
authors: J G
authors: JG
authors: de Yébenes
mesh_terms: D018389:Codon, Nonsense / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D059472:Exome / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive / Q000235:genetics; D006801:Humans; D008297:Male; D025202:Molecular Diagnostic Techniques / Q000379:methods*; D010375:Pedigree; D011506:Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013030:Spain; D015419:Spastic Paraplegia, Hereditary / Q000175:diagnosis* / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D017931:DNA Primers; D011506:Proteins; C520412:SPG11 protein, human
keywords: SPG11; genetic heterogeneity; molecular diagnosis; next-generation sequencing; spastic paraplegia; whole-exome sequencing