Communicated by Graham R. Taylor
Article first published online: 1 JUN 2010
© 2010 Wiley-Liss, Inc.
Volume 31, Issue 8, pages 918–923, August 2010
How to Cite
Lalonde, E., Albrecht, S., Ha, K. C.H., Jacob, K., Bolduc, N., Polychronakos, C., Dechelotte, P., Majewski, J. and Jabado, N. (2010), Unexpected allelic heterogeneity and spectrum of mutations in Fowler syndrome revealed by next-generation exome sequencing. Hum. Mutat., 31: 918–923. doi: 10.1002/humu.21293
The first two authors equally contributed to the manuscript.
- Issue published online: 15 JUL 2010
- Article first published online: 1 JUN 2010
- Accepted manuscript online: 1 JUN 2010 12:00AM EST
- Manuscript Accepted: 14 MAY 2010
- Manuscript Received: 16 APR 2010
- exome sequencing;
- deep sequencing;
- Fowler syndrome
Protein coding genes constitute approximately 1% of the human genome but harbor 85% of the mutations with large effects on disease-related traits. Therefore, efficient strategies for selectively sequencing complete coding regions (i.e., “whole exome”) have the potential to contribute our understanding of human diseases. We used a method for whole-exome sequencing coupling Agilent whole-exome capture to the Illumina DNA-sequencing platform, and investigated two unrelated fetuses from nonconsanguineous families with Fowler Syndrome (FS), a stereotyped phenotype lethal disease. We report novel germline mutations in feline leukemia virus subgroup C cellular-receptor-family member 2, FLVCR2, which has recently been shown to cause FS. Using this technology, we identified three types of genetic abnormalities: point-mutations, insertions-deletions, and intronic splice-site changes (first pathogenic report using this technology), in the fetuses who both were compound heterozygotes for the disease. Although revealing a high level of allelic heterogeneity and mutational spectrum in FS, this study further illustrates the successful application of whole-exome sequencing to uncover genetic defects in rare Mendelian disorders. Of importance, we show that we can identify genes underlying rare, monogenic and recessive diseases using a limited number of patients (n=2), in the absence of shared genetic heritage and in the presence of allelic heterogeneity. Hum Mutat 31:1–6, 2010. © 2010 Wiley-Liss, Inc.