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Hum Hered. 2011;72(1):45-53. doi: 10.1159/000330164. Epub 2011 Aug 18.

EX-HOM (EXome HOMozygosity): a proof of principle.

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  • 1Medical Genetics Unit, Department of Gynecological, Obstetric and Pediatric Sciences, University of Bologna, Italy. tommaso.pippucci@unibo.it



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.


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.


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.


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.

Copyright © 2011 S. Karger AG, Basel.

[PubMed - indexed for MEDLINE]
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