Journal article
Whole exome sequencing of distant relatives in multiplex families implicates rare variants in candidate genes for oral clefts
Genetics (Austin), Vol.197(3), pp.1039-1044
07/2014
DOI: 10.1534/genetics.114.165225
PMCID: PMC4096358
PMID: 24793288
Abstract
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.
Details
- Title: Subtitle
- Whole exome sequencing of distant relatives in multiplex families implicates rare variants in candidate genes for oral clefts
- Creators
- Alexandre Bureau - 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, CanadaMargaret M Parker - Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205Ingo Ruczinski - Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205Margaret A Taub - Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205Mary L Marazita - Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15219Jeffrey C Murray - Department of Pediatrics, School of Medicine, University of Iowa, Iowa City, Iowa 52242Elisabeth Mangold - Institute of Human Genetics, University of Bonn, Bonn, Germany D-53111Markus M Noethen - Institute of Human Genetics, University of Bonn, Bonn, Germany D-53111Kirsten U Ludwig - Institute of Human Genetics, University of Bonn, Bonn, Germany D-53111Jacqueline B Hetmanski - Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205Joan E Bailey-Wilson - Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore Maryland 21121Cheryl D Cropp - Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore Maryland 21121Qing Li - Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore Maryland 21121Silke Szymczak - Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore Maryland 21121Hasan Albacha-Hejazi - Hejazi Clinic, Clinic, Riyadh, Saudia Arabia 11461Khalid Alqosayer - Prime Health Clinic, Jeddah, Saudi Arabia 21511L Leigh Field - Department of Human Genetics, University of British Columbia, Vancouver, Canada V6T1Z3Yah-Huei Wu-Chou - Laboratory of Human Molecular Genetics, Chang Gung Memorial Hospital, Taipei, Taiwan 333Kimberly F Doheny - Center for Inherited Disease Research, Johns Hopkins School of Medicine, Baltimore Maryland 21224Hua Ling - Center for Inherited Disease Research, Johns Hopkins School of Medicine, Baltimore Maryland 21224Alan F Scott - Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland 21224Terri H Beaty - Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205 tbeaty1@jhu.edu
- Resource Type
- Journal article
- Publication Details
- Genetics (Austin), Vol.197(3), pp.1039-1044
- DOI
- 10.1534/genetics.114.165225
- PMID
- 24793288
- PMCID
- PMC4096358
- NLM abbreviation
- Genetics
- ISSN
- 0016-6731
- eISSN
- 1943-2631
- Publisher
- United States
- Grant note
- P50 DE016215 / NIDCR NIH HHS X01 HG006177 / NHGRI NIH HHS R01 DE014581 / NIDCR NIH HHS R01 GM083084 / NIGMS NIH HHS R01 DE016148 / NIDCR NIH HHS HHSN268200782096C / NHLBI NIH HHS U01-DE-018993 / NIDCR NIH HHS R01-DE-014581 / NIDCR NIH HHS P50-DE-016215 / NIDCR NIH HHS U01 DE018993 / NIDCR NIH HHS U01 DE020057 / NIDCR NIH HHS R01-DE-016148 / NIDCR NIH HHS
- Language
- English
- Date published
- 07/2014
- Academic Unit
- Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Pediatric Dentistry; Craniofacial Anomalies Research Center; Dental Research
- Record Identifier
- 9984025460302771
Metrics
17 Record Views