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Genetics. 2014 Jul;197(3):1039-44. doi: 10.1534/genetics.114.165225. Epub 2014 May 2.

Whole exome sequencing of distant relatives in multiplex families implicates rare variants in candidate genes for oral clefts.

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Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec and Département de Médecine Sociale et Préventive, Université Laval, Québec, QC G1V 0A6, Canada.
Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205.
Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205.
Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15219.
Department of Pediatrics, School of Medicine, University of Iowa, Iowa City, Iowa 52242.
Institute of Human Genetics, University of Bonn, Bonn, Germany D-53111.
Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore Maryland 21121.
Hejazi Clinic, Clinic, Riyadh, Saudia Arabia 11461.
Prime Health Clinic, Jeddah, Saudi Arabia 21511.
Department of Human Genetics, University of British Columbia, Vancouver, Canada V6T1Z3.
Laboratory of Human Molecular Genetics, Chang Gung Memorial Hospital, Taipei, Taiwan 333.
Center for Inherited Disease Research, Johns Hopkins School of Medicine, Baltimore Maryland 21224.
Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland 21224.
Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205


A dozen genes/regions have been confirmed as genetic risk factors for oral clefts in human association and linkage studies, and animal models argue even more genes may be involved. Genomic sequencing studies should identify specific causal variants and may reveal additional genes as influencing risk to oral clefts, which have a complex and heterogeneous etiology. We conducted a whole exome sequencing (WES) study to search for potentially causal variants using affected relatives drawn from multiplex cleft families. Two or three affected second, third, and higher degree relatives from 55 multiplex families were sequenced. We examined rare single nucleotide variants (SNVs) shared by affected relatives in 348 recognized candidate genes. Exact probabilities that affected relatives would share these rare variants were calculated, given pedigree structures, and corrected for the number of variants tested. Five novel and potentially damaging SNVs shared by affected distant relatives were found and confirmed by Sanger sequencing. One damaging SNV in CDH1, shared by three affected second cousins from a single family, attained statistical significance (P = 0.02 after correcting for multiple tests). Family-based designs such as the one used in this WES study offer important advantages for identifying genes likely to be causing complex and heterogeneous disorders.


oral clefts; pedigree studies; rare variants; whole exome sequencing

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