Objective: We provide the proof of principle that exome sequencing of only two affected siblings born to first-cousin parents is capable of directly identifying a single candidate gene for an autosomal recessive disorder. This strategy, which we call EX-HOM (EXome HOMozygosity), combines in a single step the capacity of exome sequencing to identify all the coding variants present in a genome with the property of homozygosity mapping to limit the search for candidate genes to specific chromosomal regions. Methods: We sequenced the exomes of two siblings born to first-cousin parents affected with dysmyelinating leukodystrophy and spastic paraparesis caused by a mutation in FA2H. We used exome sequencing data to identify homozygous regions shared by the two affected siblings (EX-HOM regions), compared them with the regions of maximum LOD score obtained with SNP genotyping, and selected the candidate variants within. Results: We identified regions of shared homozygosity (>1 Mb) accounting for about 290 Mb, containing only 3 candidate variants. Among these, the FA2H mutation remained the only plausible one. Conclusion: In single consanguineous pedigrees with a few affected sibs, EX-HOM can be a one-step approach to identify the candidate genetic defect, bypassing obstacles such as genetic heterogeneity and the need for large pedigrees.
© 2011 S. Karger AG, Basel
- Exome sequencing
- Homozygosity mapping
- Autosomal recessive disorders
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Medical Genetics Unit, Department of Gynecological, Obstetric and Pediatric Sciences
University of Bologna
IT–40138 Bologna (Italy)
Tel. +39 051 208 8387, E-Mail firstname.lastname@example.org
Received: January 24, 2011
Accepted after revision: June 3, 2011
Published online: August 18, 2011
Number of Print Pages : 9
Number of Figures : 3, Number of Tables : 2, Number of References : 35
Additional supplementary material is available online - Number of Parts : 1
Human Heredity (International Journal of Human and Medical Genetics)
Vol. 72, No. 1, Year 2011 (Cover Date: September 2011)
Journal Editor: Devoto M. (Philadelphia, Pa./Rome)
ISSN: 0001-5652 (Print), eISSN: 1423-0062 (Online)
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