title: High Frequency of Pathogenic Rearrangements in SPG11 and Extensive Contribution of Mutational Hotspots and Founder Alleles.
abstract: Biallelic loss-of-function mutations in SPG11 cause a wide spectrum of recessively inherited, neurodegenerative disorders including hereditary spastic paraplegia (HSP), amyotrophic lateral sclerosis, and Charcot-Marie-Tooth disease. By comprehensive screening of three large cohorts of HSP index patients, we identified 83 alleles with "small" mutations and 13 alleles that carry large genomic rearrangements. Including relevant data from previous studies, we estimate that copy number variants (CNVs) account for ∼19% of pathogenic SPG11 alleles. The breakpoints for all novel and some previously reported CNVs were determined by long-range PCR and sequencing. This revealed several Alu-associated recombination hotspots. We also found evidence for additional mutational mechanisms, including for a two-step event in which an Alu retrotransposition preceded the actual rearrangement. Apparently independent samples with identical breakpoints were analyzed by microsatellite PCRs. The resulting haplotypes suggested the existence of two rearrangement founder alleles. Our findings widen the spectra of mutations and mutational mechanisms in SPG11, underscore the pivotal role played by Alus, and are of high diagnostic relevance for a wide spectrum of clinical phenotypes including the most frequent form of recessive HSP.
authors.affiliation: Department of Clinical Chemistry and Laboratory Medicine, Jena University Hospital, Jena, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Günther
authors.affiliation: Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland.
authors.forename: Ewelina
authors.initials: E
authors.lastname: Elert-Dobkowska
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University Hospital of Tuebingen, Tuebingen, Germany.
authors.forename: Anne S
authors.initials: AS
authors.lastname: Soehn
authors.affiliation: Center for Human Genetics, and Department of Human Genetics, University of Regensburg, Regensburg, Germany.
authors.forename: Sophie
authors.initials: S
authors.lastname: Hinreiner
authors.affiliation: Division of Clinical and Metabolic Genetics, Department of Paediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Grace
authors.initials: G
authors.lastname: Yoon
authors.affiliation: Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany.
authors.forename: Raoul
authors.initials: R
authors.lastname: Heller
authors.affiliation: Institute of Human Genetics, University of Lübeck, Lübeck, Germany.
authors.forename: Yorck
authors.initials: Y
authors.lastname: Hellenbroich
authors.affiliation: Department of Human Genetics, Jena University Hospital, Jena, Germany.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Hübner
authors.affiliation: Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Peter N
authors.initials: PN
authors.lastname: Ray
authors.affiliation: Center for Human Genetics, and Department of Human Genetics, University of Regensburg, Regensburg, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Hehr
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University Hospital of Tuebingen, Tuebingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Bauer
authors.affiliation: Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Sulek
authors.affiliation: Department of Clinical Chemistry and Laboratory Medicine, Jena University Hospital, Jena, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Beetz
mesh_terms: D000483:Alleles; D020087:Alu Elements; D056905:Chromosome Breakpoints; D002877:Chromosomes, Human / Q000235:genetics; D056915:DNA Copy Number Variations; D018703:Founder Effect; D006801:Humans; D009154:Mutation; D011506:Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics*
chemical_list: D011506:Proteins; C520412:SPG11 protein, human
keywords: Copy number variant; Founder allele; Mutational hotspot; SPG11