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EX-HOM (EXome HOMozygosity): A Proof of PrinciplePippucci T.a · Benelli M.c, d, e · Magi A.d, e, f · Martelli P.L.b · Magini P.a · Torricelli F.d · Casadio R.b · Seri M.a · Romeo G.a
aMedical Genetics Unit, Department of Gynecological, Obstetric and Pediatric Sciences, and bLaboratory of Biocomputing, CIRB/Department of Biology, University of Bologna, Bologna, cINFN, National Institute for Nuclear Physics, Section of Florence, dDiagnostic Genetic Unit, Careggi Hospital, AOUC, eCenter for the Study of Complex Dynamics, and fDepartment of Medical and Surgical Critical Care, University of Florence, Florence, Italy Corresponding Author
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
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.
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