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.

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

PIPPUCCI, TOMMASO;MARTELLI, PIER LUIGI;MAGINI, PAMELA;CASADIO, RITA;SERI, MARCO;ROMEO, GIOVANNI
2011

Abstract

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.
Pippucci T.; Benelli M.; Magi A.; Martelli P.L.; Magini P.; Torricelli F.; Casadio R.; Seri M.; Romeo G.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11585/107009
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