Communicated by Hamish S. Scott
Do Not Trust the Pedigree: Reduced and Sex-Dependent Penetrance at a Novel Mutation Hotspot in ATL1 Blurs Autosomal Dominant Inheritance of Spastic Paraplegia
Article first published online: 5 APR 2013
© 2013 Wiley Periodicals, Inc.
Volume 34, Issue 6, pages 860–863, June 2013
How to Cite
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. (2013), Do Not Trust the Pedigree: Reduced and Sex-Dependent Penetrance at a Novel Mutation Hotspot in ATL1 Blurs Autosomal Dominant Inheritance of Spastic Paraplegia. Hum. Mutat., 34: 860–863. doi: 10.1002/humu.22309
Contract grant sponsors: Tom-Wahlig-Foundation (project 26); the Spanish Fondo de Investigaciones Sanitarias Grant (FIS 10/01070-FEDER); the NIH (5R01NS072248, 5R01NS054132); the IZKF program of University of Tübingen (1970–0–0).
- Issue published online: 20 MAY 2013
- Article first published online: 5 APR 2013
- Accepted manuscript online: 8 MAR 2013 02:55PM EST
- Manuscript Accepted: 28 FEB 2013
- Manuscript Received: 7 JAN 2013
- Spanish Fondo de Investigaciones Sanitarias. Grant Number: FIS 10/01070-FEDER
- NIH. Grant Numbers: 5R01NS072248, 5R01NS054132
- University of Tübingen. Grant Number: 1970–0–0
- inheritance pattern;
- spastic paraplegia
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.