title: Whole exome association of rare deletions in multiplex oral cleft families.
abstract: By sequencing the exomes of distantly related individuals in multiplex families, rare mutational and structural changes to coding DNA can be characterized and their relationship to disease risk can be assessed. Recently, several rare single nucleotide variants (SNVs) were associated with an increased risk of nonsyndromic oral cleft, highlighting the importance of rare sequence variants in oral clefts and illustrating the strength of family-based study designs. However, the extent to which rare deletions in coding regions of the genome occur and contribute to risk of nonsyndromic clefts is not well understood. To identify putative structural variants underlying risk, we developed a pipeline for rare hemizygous deletions in families from whole exome sequencing and statistical inference based on rare variant sharing. Among 56 multiplex families with 115 individuals, we identified 53 regions with one or more rare hemizygous deletions. We found 45 of the 53 regions contained rare deletions occurring in only one family member. Members of the same family shared a rare deletion in only eight regions. We also devised a scalable global test for enrichment of shared rare deletions.
authors.affiliation: Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore MD, USA.
authors.forename: Jack
authors.initials: J
authors.lastname: Fu
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore MD, USA.
authors.forename: Terri H
authors.initials: TH
authors.lastname: Beaty
authors.affiliation: Center for Inherited Disease Research, Johns Hopkins School of Medicine, Baltimore MD, USA.|Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore MD, USA.
authors.forename: Alan F
authors.initials: AF
authors.lastname: Scott
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore MD, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Hetmanski
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Parker
authors.affiliation: Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Joan E Bailey
authors.initials: JE
authors.lastname: Wilson
authors.affiliation: Department of Oral Biology, Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, PA, USA.
authors.forename: Mary L
authors.initials: ML
authors.lastname: Marazita
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Mangold
authors.affiliation: Dr. Hejazi Clinic, Damascus, Syrian Arab Republic.
authors.forename: Hasan
authors.initials: H
authors.lastname: Albacha-Hejazi
authors.affiliation: Department of Pediatrics, School of Medicine, University of Iowa, IA, USA.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Murray
authors.affiliation: Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec and Département de Médecine Sociale et Préventive, Université Laval, Québec, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Bureau
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore MD, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Carey
authors.affiliation: Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore MD, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Cristiano
authors.affiliation: Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore MD, USA.
authors.forename: Ingo
authors.initials: I
authors.lastname: Ruczinski
authors.affiliation: Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Scharpf
mesh_terms: D000465:Algorithms; D015415:Biomarkers / Q000032:analysis*; D002972:Cleft Palate / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005190:Family; D005260:Female; D017353:Gene Deletion; D014644:Genetic Variation / Q000235:genetics*; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male
chemical_list: D015415:Biomarkers
keywords: copy number; multiplex families; oral clefts; rare variants; structural variants