Replication of Genome Wide Association Identified Candidate Genes Confirm the Role of Common and Rare Variants in<scp>PAX</scp>7and<scp>VAX</scp>1in the Etiology of Nonsyndromic CL(P)

Butali, Azeez; Suzuki, Satoshi; Cooper, Margaret E.; Mansilla, Adela M.; Cuenco, Karen T.; Leslie, Elizabeth J.; Suzuki, Yasushi; Niimi, Teruyuki; Yamamoto, Masahiko; Ayanga, Gongorjav; Erkhembaatar, Tudevdorj; Furukawa, Hiroyuki; Fujiwawa, Kumiko; Imura, Hideto; Petrin, Aline; Natsume, Nagato; Beaty, Terri H.; Marazita, Mary L.; Murray, Jeffery C.

doi:10.1002/ajmg.a.35749

Cited by 63 publications

(56 citation statements)

References 41 publications

(44 reference statements)

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“…There is also the need to functionally validate the pathogenicity or otherwise of these variants in vivo. Rare variants in ARHGAP29 (Leslie et al 2012), PAX7 and VAX1 (Butali et al 2013;Leslie et al 2015), BMP4 (Suzuki et al 2009), FOXE1 (Moreno et al 2009), MAFB , and MSX1 (Liang et al 2012) have been observed in NSOFC cases.…”

Section: Discussionmentioning

confidence: 99%

Association Studies and Direct DNA Sequencing Implicate Genetic Susceptibility Loci in the Etiology of Nonsyndromic Orofacial Clefts in Sub-Saharan African Populations

et al. 2016

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Orofacial clefts (OFCs) are congenital dysmorphologies of the human face and oral cavity, with a global incidence of 1 per 700 live births. These anomalies exhibit a multifactorial pattern of inheritance, with genetic and environmental factors both playing crucial roles. Many loci have been implicated in the etiology of nonsyndromic cleft lip with or without cleft palate (NSCL/P) in populations of Asian and European ancestries, through genome-wide association studies and candidate gene studies. However, few populations of African descent have been studied to date. Here, the authors show evidence of an association of some loci with NSCL/P and nonsyndromic cleft palate only (NSCPO) in cohorts from Africa (Ghana, Ethiopia, and Nigeria). The authors genotyped 48 single-nucleotide polymorphisms that were selected from previous genome-wide association studies and candidate gene studies. These markers were successfully genotyped on 701 NSCL/P and 163 NSCPO cases, 1,070 unaffected relatives, and 1,078 unrelated controls. The authors also directly sequenced 7 genes in 184 nonsyndromic OFC (NSOFC) cases and 96 controls from Ghana. Population-specific associations were observed in the casecontrol analyses of the subpopulations, with West African subpopulations (Ghana and Nigeria) showing a similar pattern of associations. In meta-analyses of the case-control cohort, PAX7 (rs742071, P = 5.10 × 10 -3 ), 8q24 (rs987525, P = 1.22 × 10 -3 ), and VAX1 (rs7078160, P = 0.04) were nominally associated with NSCL/P, and MSX1 (rs115200552, P = 0.01), TULP4 (rs651333, P = 0.04), CRISPLD2 (rs4783099, P = 0.02), and NOG1 (rs17760296, P = 0.04) were nominally associated with NSCPO. Moreover, 7 loci exhibited evidence of threshold overtransmission in NSOFC cases through the transmission disequilibrium test and through analyses of the family-based association for disease traits. Through DNA sequencing, the authors also identified 2 novel, rare, potentially pathogenic variants (p.Asn323Asp and p.Lys426IlefsTer6) in ARHGAP29. In conclusion, the authors have shown evidence for the association of many loci with NSCL/P and NSCPO. To the best of this knowledge, this study is the first to demonstrate any of these association signals in any African population.

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Section: Discussionmentioning

confidence: 99%

Association Studies and Direct DNA Sequencing Implicate Genetic Susceptibility Loci in the Etiology of Nonsyndromic Orofacial Clefts in Sub-Saharan African Populations

et al. 2016

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“…As a result, we focused on Vax1 and Sfrp family genes. Recent studies reported significant genetic associations between VAX1 mutations and CL/P in humans (43)(44)(45). Furthermore, Vax1-null mice display cleft palate (46).…”

Section: Disruption Of the Shh Signaling Gradient During Craniofacialmentioning

confidence: 99%

Disrupting hedgehog and WNT signaling interactions promotes cleft lip pathogenesis

Kurosaka¹,

Iulianella²,

Williams³

et al. 2014

J. Clin. Invest.

101

126

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Cleft lip, which results from impaired facial process growth and fusion, is one of the most common cranio facial birth defects. Many genes are known to be involved in the etiology of this disorder; however, our under standing of cleft lip pathogenesis remains incomplete. In the present study, we uncovered a role for sonic hedgehog (SHH) signaling during lip fusion. Mice carrying compound mutations in hedgehog acyltransferase (Hhat) and patched1 (Ptch1) exhibited perturbations in the SHH gradient during frontonasal development, which led to hypoplastic nasal process outgrowth, epithelial seam persistence, and cleft lip. Further investi gation revealed that enhanced SHH signaling restricts canonical WNT signaling in the lambdoidal region by promoting expression of genes encoding WNT inhibitors. Moreover, reduction of canonical WNT signaling perturbed p63/interferon regulatory factor 6 (p63/IRF6) signaling, resulting in increased proliferation and decreased cell death, which was followed by persistence of the epithelial seam and cleft lip. Consistent with our results, mutations in genes that disrupt SHH and WNT signaling have been identified in both mice and humans with cleft lip. Collectively, our data illustrate that altered SHH signaling contributes to the etiology and pathogenesis of cleft lip through antagonistic interactions with other gene regulatory networks, including the canonical WNT and p63/IRF6 signaling pathways.

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“…Recently, there has been a resurgence of candidate gene resequencing studies following the genome-wide studies described above to provide evidence that the nearby genes are causal for OFCs. Briefly, these studies have provided evidence for GREM1 [68], MAFB [50], and ARHGAP29 [69] and have examined PAX7 [70], VAX1 [71], ABCA4 [50], and NOG [68]. Sanger sequencing has been the approach taken for these studies but is inefficient for large intervals and relies on a priori knowledge to select genes for sequencing.…”

Section: Next-generation Sequencing Of Ofcsmentioning

confidence: 98%

Genetics of Orofacial Cleft Birth Defects

Leslie

Marazita

2015

Curr Genet Med Rep

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Orofacial cleft birth defects (OFCs) are the most common facial birth defects and among the most common of all birth defects. OFCs can occur as isolated, nonsyndromic events or as part of Mendelian syndromes. Notably, many genes that contribute to the etiology of these disorders, both syndromic and nonsyndromic, have now been identified after decades of research using multiple genetic approaches. The pace of gene identification has significantly increased recently due to advances in sequencing and genotyping technologies. Multiple genome-wide association studies of nonsyndromic OFCs have identified genomic regions that were followed by successful targeted sequencing and functional studies. In addition, other genomic techniques, primarily wholeexome sequencing, have also identified the major genes for many syndromic forms of OFC. Future progress will hinge on identifying functional variants, investigation of pathway and other interactions, and inclusion of phenotypic and ethnic diversity in studies.

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Replication of Genome Wide Association Identified Candidate Genes Confirm the Role of Common and Rare Variants inPAX7andVAX1in the Etiology of Nonsyndromic CL(P)

Cited by 63 publications

References 41 publications

Association Studies and Direct DNA Sequencing Implicate Genetic Susceptibility Loci in the Etiology of Nonsyndromic Orofacial Clefts in Sub-Saharan African Populations

Association Studies and Direct DNA Sequencing Implicate Genetic Susceptibility Loci in the Etiology of Nonsyndromic Orofacial Clefts in Sub-Saharan African Populations

Disrupting hedgehog and WNT signaling interactions promotes cleft lip pathogenesis

Genetics of Orofacial Cleft Birth Defects

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