Do not trust the pedigree: reduced and sex-dependent penetrance at a novel mutation hotspot in ATL1 blurs autosomal dominant inheritance of spastic paraplegia
Autor: | Rita Eva Varga, Christian Beetz, Hicham Fadel, Michael A. Gonzalez, Josep Gamez, Fiorella Speziani, Rebecca Schüle, Irene Valenzuela, Peter Nürnberg, Galina Rudenskaia, Stephan Züchner, Janine Altmüller, Victoria Alvarez, Gudrun Nürnberg, James Y. Garbern, Holger Thiele |
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Rok vydání: | 2013 |
Předmět: |
Male
Candidate gene Adolescent DNA Mutational Analysis Molecular Sequence Data Biology Consanguinity Missing heritability problem GTP-Binding Proteins Genes X-Linked Genetics Inheritance Patterns Humans Amino Acid Sequence Child Gene Genetics (clinical) Exome sequencing Genes Dominant Base Sequence Genetic heterogeneity Spastic Paraplegia Hereditary Haplotype Membrane Proteins Penetrance Pedigree Child Preschool Mutation Female Sequence Alignment |
Zdroj: | Human mutation. 34(6) |
ISSN: | 1098-1004 |
Popis: | 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. |
Databáze: | OpenAIRE |
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