Dataset Information

Analysis of sequence data to identify potential risk variants for oral clefts in multiplex families.

ABSTRACT:

Background

Nonsyndromic oral clefts are craniofacial malformations, which include cleft lip with or without cleft palate. The etiology for oral clefts is complex with both genetic and environmental factors contributing to risk. Previous genome-wide association (GWAS) studies have identified multiple loci with small effects; however, many causal variants remain elusive.

Methods

In this study, we address this by specifically looking for rare, potentially damaging variants in family-based data. We analyzed both whole exome sequence (WES) data and whole genome sequence (WGS) data in multiplex cleft families to identify variants shared by affected individuals.

Results

Here we present the results from these analyses. Our most interesting finding was from a single Syrian family, which showed enrichment of nonsynonymous and potentially damaging rare variants in two genes: CASP9 and FAT4.

Conclusion

Neither of these candidate genes has previously been associated with oral clefts and, if confirmed as contributing to disease risk, may indicate novel biological pathways in the genetic etiology for oral clefts.

SUBMITTER: Holzinger ER

PROVIDER: S-EPMC5606860 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Publications

Analysis of sequence data to identify potential risk variants for oral clefts in multiplex families.

Holzinger Emily R ER Li Qing Q Parker Margaret M MM Hetmanski Jacqueline B JB Marazita Mary L ML Mangold Elisabeth E Ludwig Kerstin U KU Taub Margaret A MA Begum Ferdouse F Murray Jeffrey C JC Albacha-Hejazi Hasan H Alqosayer Khalid K Al-Souki Giath G Albasha Hejazi Abdullatiff A Scott Alan F AF Beaty Terri H TH Bailey-Wilson Joan E JE

Molecular genetics & genomic medicine 20170809 5

<h4>Background</h4>Nonsyndromic oral clefts are craniofacial malformations, which include cleft lip with or without cleft palate. The etiology for oral clefts is complex with both genetic and environmental factors contributing to risk. Previous genome-wide association (GWAS) studies have identified multiple loci with small effects; however, many causal variants remain elusive.<h4>Methods</h4>In this study, we address this by specifically looking for rare, potentially damaging variants in family- ...[more]

PMID: 28944239

Similar Datasets

Project description:BackgroundAlcohol use disorder (AUD) runs in families and is accompanied by genetic variation. Some families exhibit an extreme susceptibility in which multiple cases are found and often with an early onset of the disorder. Large scale genome-wide association studies have identified several genes with impressive statistical probabilities. Most of these genes are common variants. Our goal was to perform exome sequencing in families characterized by multiple cases (multiplex families) to determine if rare variants might be segregating with disease status.MethodsA case-control approach was used to leverage the power of a large control sample of unrelated individuals (N = 8,983) with exome sequencing [Institute for Genomic Medicine (IGM)], for comparison with probands with AUD (N = 53) from families selected for AUD multiplex status. The probands were sequenced at IGM using similar protocols to those used for the archival controls. Specifically, the presence of a same-sex pair of adult siblings with AUD was the minimal criteria for inclusion. Using a gene-based collapsing analysis strategy, a search for qualifying variants within the sequence data was undertaken to identify ultra-rare non-synonymous variants.ResultsWe searched 18,666 protein coding genes to identify an excess of rare deleterious genetic variation using whole exome sequence data in the 53 AUD individuals from a total of 282 family members. To complete a case/control analysis of unrelated individuals, probands were compared to unrelated controls. Case enrichment for 16 genes with significance at 10-4 and one at 10-5 are plausible candidates for follow-up studies. Six genes were ultra rare [minor allele frequency (MAF) of 0.0005]: CDSN, CHRNA9, IFT43, TLR6, SELENBP1, and GMPPB. Eight genes with MAF of 0.001: ZNF514, OXGR1, DIEXF, TMX4, MTBP, PON2, CRHBP, and ANKRD46 were identified along with three protein-truncating variants associated with loss-of-function: AGTRAP, ANKRD46, and PPA1. Using an ancestry filtered control group (N = 2,814), nine genes were found; three were also significant in the comparison to the larger control group including CHRNA9 previously implicated in alcohol and nicotine dependence.ConclusionThis study implicates ultra-rare loss-of-function genes in AUD cases. Among the genes identified include those previously reported for nicotine and alcohol dependence (CHRNA9 and CRHBP).

Dataset Information

Analysis of sequence data to identify potential risk variants for oral clefts in multiplex families.

Background

Methods

Results

Conclusion

Publications

Analysis of sequence data to identify potential risk variants for oral clefts in multiplex families.

Similar Datasets

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