Do not trust the pedigree: reduced and sex-dependent penetrance at a novel mutation hotspot in ATL1 blurs autosomal dominant inheritance of spastic paraplegia

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Item Type:	Article
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
Creators Name:	Varga, R.E., Schüle, R., Fadel, H., Valenzuela, I., Speziani, F., Gonzalez, M., Rudenskaia, G., Nürnberg, G., Thiele, H., Altmüller, J., Alvarez, V., Gamez, J., Garbern, J.Y., Nürnberg, P., Zuchner, S. and Beetz, C.
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.
Keywords:	ATL1, Inheritance Pattern, Pedigree, Penetrance, Spastic Paraplegia
Source:	Human Mutation
ISSN:	1059-7794
Publisher:	Wiley
Volume:	34
Number:	6
Page Range:	860-863
Date:	20 May 2013
Official Publication:	https://doi.org/10.1002/humu.22309
PubMed:	View item in PubMed

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