Confirming genes influencing risk to cleft lip with/without cleft palate in a case–parent trio study

Beaty, Terri H.; Taub, Margaret A.; Scott, Alan F.; Murray, Jeffrey C.; Marazita, Mary L.; Schwender, Holger; Parker, Margaret M.; Hetmanski, Jacqueline B.; Balakrishnan, Poojitha; Mansilla, M. Adela; Mangold, Elisabeth; Ludwig, Kerstin U.; Nöethen, Markus M.; Rubini, Michele; Elcioğlu, Nursel; Ruczinski, Ingo

doi:10.1007/s00439-013-1283-6

Cited by 134 publications

(131 citation statements)

References 26 publications

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“…Recent studies have reported association of nsCL/P with many loci throughout the genome [11][12][13][14][39][40][41][42] . Replication of those results on various populations and the investigation of mechanisms by which these variants influence cleft susceptibility are crucial for better understanding of genetic architecture of nsCL/P.…”

Section: Resultsmentioning

confidence: 99%

Polymorphisms at 1q32, 8q24, and 17q22 loci are associated with nonsyndromic cleft lip with or without cleft palate risk in the Slovak population

Salagovic¹,

Klimčáková²,

Zabavnikova³

et al. 2017

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Background. Nonsyndromic cleft lip with or without cleft palate (nsCL/P) is the most common orofacial birth defect with an aetiology involving both genetic and environmental factors. Genome-wide association studies (GWAS) have identified several genomic susceptibility regions for nsCL/P. In the present study, the three well established single nucleotide polymorphisms (SNPs) identified by GWAS (rs987525 at 8q24, rs7078160 at 10q25, and rs227731 at 17q22 loci) and one SNP identified by candidate gene study (rs642961 in IRF6 gene at 1q32 locus) were analysed for an association with nsCL/P in Slovak population. Methods. Nucleotide variants were genotyped in 165 nsCL/P patients and 326 unaffected controls. All variants of interest were genotyped using high-resolution melting analysis after real-time PCR. Results. We found significant differences between patient and control groups with respect to the allele and genotype frequencies for the SNPs at the 1q32, 8q24, and 17q22 loci. SNP at the 10q25 locus showed a trend toward association with nsCL/P risk. Conclusions.The results suggest that SNPs at the 1q32, 8q24 and 17q22 loci may contribute to the nsCL/P risk in Slovak population.

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Section: Resultsmentioning

confidence: 99%

Polymorphisms at 1q32, 8q24, and 17q22 loci are associated with nonsyndromic cleft lip with or without cleft palate risk in the Slovak population

Salagovic¹,

Klimčáková²,

Zabavnikova³

et al. 2017

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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“…In this work, we focused on SNVs in 334 autosomal candidate genes for oral clefts (Jugessur et al 2009) plus 14 recently confirmed genes/regions yielding genome-wide significance in a meta-analysis (Ludwig et al 2012) and a replication study (Beaty et al 2013). Thus, 348 candidate genes were considered.…”

Section: Analyzing Called Variantsmentioning

confidence: 99%

“…Both genome-wide linkage and association studies have shown multiple genes influence risk to oral clefts (Mangold et al 2011;Marazita 2012) and recently at least a dozen different genes have been identified as genetic risk factors in genome-wide association studies (GWASs) (Ludwig et al 2012;Beaty et al 2013). Few of these genes, however, have causal variants identified.…”

mentioning

confidence: 99%

“…Our goal was to identify rare potentially causal variants among a large list of candidate genes for oral clefts [334 biologically plausible, autosomal candidate genes for oral clefts assembled by Jugessur et al (2009) supplemented with confirmed GWAS "hits" (Ludwig et al 2012;Beaty et al 2013)] from whole exome sequencing (WES) data on affected individuals drawn from multiplex families originally ascertained for linkage studies. Our inferences assume damaging RVs shared between such distant affected relatives may be causal.…”

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confidence: 99%

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Whole Exome Sequencing of Distant Relatives in Multiplex Families Implicates Rare Variants in Candidate Genes for Oral Clefts

et al. 2014

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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.

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“…Although folic acid and smoking were found to influence OC outcomes, no significant interaction was demonstrated with the C677T variant. Beaty et al 20 found some evidence for geneenvironment interaction using available data on maternal smoking during pregnancy in European case-parent trios. The genes involved were GRID2 and ELAVL2.…”

Section: Environmental Factors and Geneenvironment Interactionmentioning

confidence: 99%

The potential for next generation sequencing to characterise the genetic variation underlying nonsyndromic cleft lip and palate phenotypes

Collins¹,

Arias²,

Pengelly³

et al. 2013

OA Genetics

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Genetics of Complex DiseasesAbstract Introduction Next-generation sequencing is revolutionising the study of genetic variation and its role in disease. Individual DNA samples can now be sequenced cost-effectively enabling analysis of the complete spectrum of genetic variation. This technology has the potential to contribute significantly to the understanding of non-syndromic cleft lip and/or palate. This condition occurs with relatively high frequency and only a proportion of the underlying genetic causal factors have been identified. Many of the genes implicated have been found through genome-wide association studies but further progress is limited because these approaches consider only common genetic variants and neglect rarer variations. Because many of the causal genetic variants remain unknown, the role of gene-environment and genegene interaction is difficult to characterise. The identification of novel, low frequency, variants will provide new insights into the biological mechanisms and pathways involved in the condition. Sequence-based analysis will also be invaluable for fine mapping causal variants in the larger regions already identified by linkage and association studies for which positive identification of causal genetic variants has proven difficult. This review considers the available evidence for the genes involved and current understanding of how genetic variation interacts with environmental factors known to influence risk. Only by characterising the underlying genetic factors will the effort to understand gene-environment interaction and underlying functional processes be successful. Conclusion Success with next-generation sequencing will lead to improvements in prediction, prevention, and treatment for cleft lip and palate patients. IntroductionNext-generation sequencing (NGS) is revolutionising genomics 1 and this trend of increasingly significant impact is likely to continue. Most importantly, NGS provides a route to characterising and understanding the role of genetic variation in disease. This is important because evidence from genome-wide association studies (GWAS) suggests that much of the heritability underlying complex disease phenotypes is not explained by common deleterious genetic variants with small effect sizes 2 . NGS enables new analytical strategies, which are not achievable through genome-wide association studies. These include: the identification of the complete complement of DNA variants in samples (across the allele frequency spectrum); tests on the burden of rare variation(do specific genes contain many rare variants which collectively impair gene function?); the identification of de novo mutations and the genes underlying rare Mendelian forms of disease; fine mapping of causal variants within broader regions identified by linkage and/or association and the characterisation of important structural variation, such as differences in copy number, which may contribute to disease.Orofacial cleft lip and/or palate (CLP) represents a complex phenotype for which NGS offers the po...

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Confirming genes influencing risk to cleft lip with/without cleft palate in a case–parent trio study

Cited by 134 publications

References 26 publications

Polymorphisms at 1q32, 8q24, and 17q22 loci are associated with nonsyndromic cleft lip with or without cleft palate risk in the Slovak population

Polymorphisms at 1q32, 8q24, and 17q22 loci are associated with nonsyndromic cleft lip with or without cleft palate risk in the Slovak population

Whole Exome Sequencing of Distant Relatives in Multiplex Families Implicates Rare Variants in Candidate Genes for Oral Clefts

The potential for next generation sequencing to characterise the genetic variation underlying nonsyndromic cleft lip and palate phenotypes

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