title: Do not trust the pedigree: reduced and sex-dependent penetrance at a novel mutation hotspot in ATL1 blurs autosomal dominant inheritance of spastic paraplegia.
abstract: The hereditary spastic paraplegias (HSPs), a group of neurodegenerative movement disorders, are among the genetically most heterogeneous clinical conditions. Still, the more than 50 forms known so far apparently explain less than 80% of cases. The present study identified two large HSP families, which seemed to show an autosomal recessive and an X-linked inheritance pattern. A set of genetic analyses including exome sequencing revealed plausible mutations only when assuming incomplete/sex-dependent penetrance of adjacent alterations in the autosomal dominant HSP gene ATL1 (c.1243C>T and c.1244G>A, respectively). By screening of additional HSP patients for the presence of these alterations, we identified three more cases and obtained additional evidence for reduced penetrance. Bisulfate sequencing and haplotype analysis indicated that c.1243C and c.1244G constitute a mutational hotspot. Our findings suggest that misinterpretation of inheritance patterns and, consequently, misselection of candidate genes to be screened in gene-focused approaches contribute to the apparently missing heritability in HSP and, potentially, in other genetically heterogeneous disorders.
authors.affiliation: Department of Clinical Chemistry, Jena University Hospital, Jena, Germany.
authors.forename: Rita-Eva
authors.initials: RE
authors.lastname: Varga
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schüle
authors.forename: Hicham
authors.initials: H
authors.lastname: Fadel
authors.forename: Irene
authors.initials: I
authors.lastname: Valenzuela
authors.forename: Fiorella
authors.initials: F
authors.lastname: Speziani
authors.forename: Michael
authors.initials: M
authors.lastname: Gonzalez
authors.forename: Galina
authors.initials: G
authors.lastname: Rudenskaia
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.forename: Victoria
authors.initials: V
authors.lastname: Alvarez
authors.forename: Josep
authors.initials: J
authors.lastname: Gamez
authors.forename: James Y
authors.initials: JY
authors.lastname: Garbern
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Stephan
authors.initials: S
authors.lastname: Zuchner
authors.forename: Christian
authors.initials: C
authors.lastname: Beetz
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005260:Female; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D005799:Genes, Dominant; D050172:Genes, X-Linked; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D016415:Sequence Alignment; D015419:Spastic Paraplegia, Hereditary / Q000175:diagnosis* / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; C440006:ATL1 protein, human; D019204:GTP-Binding Proteins