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

TitleWhole exome sequencing of distant relatives in multiplex families implicates rare variants in candidate genes for oral clefts.
Publication TypeJournal Article
Year of Publication2014
AuteursBureau, A, Parker, MM, Ruczinski, I, Taub, MA, Marazita, ML, Murray, JC, Mangold, E, Noethen, MM, Ludwig, KU, Hetmanski, JB, Bailey-Wilson, JE, Cropp, CD, Li, Q, Szymczak, S, Albacha-Hejazi, H, Alqosayer, K, L Field, L, Wu-Chou, Y-H, Doheny, KF, Ling, H, Scott, AF, Beaty, TH
JournalGenetics
Volume197
Issue3
Pagination1039-44
Date Published2014 Jul
ISSN1943-2631
KeywordsCadherins, Cleft Palate, Ethnic Groups, Exome, Family, Female, Genetic Association Studies, Humans, Male, Mutation, Pedigree, Reproducibility of Results, Sequence Analysis, DNA
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.

DOI10.1534/genetics.114.165225
Alternate JournalGenetics
PubMed ID24793288
PubMed Central IDPMC4096358
Grant ListU01-DE-018993 / DE / NIDCR NIH HHS / United States
U01 DE018993 / DE / NIDCR NIH HHS / United States
R01 GM083084 / GM / NIGMS NIH HHS / United States
X01 HG006177 / HG / NHGRI NIH HHS / United States
R01 DE014581 / DE / NIDCR NIH HHS / United States
HHSN268200782096C / HG / NHGRI NIH HHS / United States
R01 DE016148 / DE / NIDCR NIH HHS / United States
R01-DE-016148 / DE / NIDCR NIH HHS / United States
P50-DE-016215 / DE / NIDCR NIH HHS / United States
R01-DE-014581 / DE / NIDCR NIH HHS / United States
P50 DE016215 / DE / NIDCR NIH HHS / United States
U01 DE020057 / DE / NIDCR NIH HHS / United States