title: EX-HOM (EXome HOMozygosity): a proof of principle.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Medical Genetics Unit, Department of Gynecological, Obstetric and Pediatric Sciences, University of Bologna, Italy. tommaso.pippucci@unibo.it
authors.forename: Tommaso
authors.initials: T
authors.lastname: Pippucci
authors.forename: Matteo
authors.initials: M
authors.lastname: Benelli
authors.forename: Alberto
authors.initials: A
authors.lastname: Magi
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Martelli
authors.forename: Pamela
authors.initials: P
authors.lastname: Magini
authors.forename: Francesca
authors.initials: F
authors.lastname: Torricelli
authors.forename: Rita
authors.initials: R
authors.lastname: Casadio
authors.forename: Marco
authors.initials: M
authors.lastname: Seri
authors.forename: Giovanni
authors.initials: G
authors.lastname: Romeo
mesh_terms: D005091:Exons / Q000235:genetics*; D005808:Genes, Recessive / Q000235:genetics*; D056726:Genetic Association Studies / Q000379:methods*; D014644:Genetic Variation; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007558:Italy; D008126:Lod Score; D006899:Mixed Function Oxygenases / Q000235:genetics; D020336:Paraparesis, Spastic / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017422:Sequence Analysis, DNA; D035781:Siblings
chemical_list: D006899:Mixed Function Oxygenases; C019081:fatty acid alpha-hydroxylase