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Rita-Eva Varga, Rebecca Schüle, Hicham Fadel, Irene Valenzuela, Fiorella Speziani, Michael Gonzalez, Galina Rudenskaia, Gudrun Nürnberg, Holger Thiele, Janine Altmüller, Victoria Alvarez, Josep Gamez, James Y. Garbern, Peter Nürnberg, Stephan Zuchner and Christian Beetz Do Not Trust the Pedigree: Reduced and Sex-Dependent Penetrance at a Novel Mutation Hotspot in ATL1 Blurs Autosomal Dominant Inheritance of Spastic Paraplegia Human Mutation 34

Version of Record online: 5 APR 2013 | DOI: 10.1002/humu.22309

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Inheritance patterns usually guide gene selection in mutational screening strategies. By whole exome sequencing of index cases with apparently novel forms of spastic paraplegia, we identify a mutational hotspot in the known dominant gene ATL1 and show that corresponding alterations are associated with a highly reduced and partially sex-dependent risk of developing the disease. Our findings suggest that misleading family history may contribute to missing heritability in genetically heterogeneous disorders.

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