Shared molecular networks in orofacial and neural tube development

Kousa, Youssef A.; Mansour, Tamer; Seada, Haitham; Matoo, Samaneh; Schutte, Brian C.

doi:10.1002/bdra.23598

Cited by 21 publications

(23 citation statements)

References 69 publications

(85 reference statements)

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“…This is particularly interesting, because NTDs and OFCs appear to share some aetiological features: They both occur when tissues in the midline fail to fuse completely during embryonic development [52]; they co-occur in the same individuals and in related individuals more than would be expected by chance [53]; they share several environmental risk factors [2,3,54,55]. Our findings further support recent evidence of an overlap in the molecular networks associated with OFCs and NTDs [56].…”

Section: Discussionsupporting

confidence: 85%

Distinct blood DNA methylation profiles in subtypes of orofacial cleft

Sharp

Davies

et al. 2017

Preprint

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BackgroundThere is evidence that different subtypes of orofacial cleft have distinct aetiologies, although the precise molecular mechanisms underlying these are unknown. Given the key role of epigenetic processes such as DNA methylation in embryonic development, it is likely that aberrant DNA methylation may also play a part in the development of orofacial clefts.MethodsIn this study, we explored whether blood samples from children with different cleft subtypes showed distinct DNA methylation profiles.In whole blood samples from 150 children from the Cleft Collective cohort study, we measured DNA methylation at over 450,000 sites on the genome. We then carried out epigenome-wide association studies (EWAS) to test the association between methylation at each site and cleft subtype (cleft lip only CLO n=50; cleft palate only CPO n=50; cleft lip and palate CLP n=50).ResultsWe found four genomic regions differentially methylated in CLO compared to CLP, 17 in CPO compared to CLP and 294 in CPO compared to CLO. These regions included several mapping to genes that have previously been implicated in the development of orofacial clefts (for example, TBX1, COL11A2, HOXA2, PDGFRA) and over 250 novel associations.ConclusionOur finding of distinct methylation profiles in different cleft subtypes might reflect differences in their aetiologies, with DNA methylation either playing a causal role in development of OFC subtypes or reflecting causal genetic or environmental factors.

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Section: Discussionsupporting

confidence: 85%

Distinct blood DNA methylation profiles in subtypes of orofacial cleft

Sharp

Davies

et al. 2017

Preprint

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“…In mouse, loss of Grhl3 results in spina bifida and in abnormal oral periderm leading to a cleft palate in 17% of embryos confirming a multifaceted role of this gene in both neurulation and craniofacial development. A recent study based on literature review and bioinformatics analyses have identified common regulatory factors in orofacial and neural tube development, including GRHL3 (Kousa, Mansour, Seada, Matoo, & Schutte, ). We have previously reported that a de novo variant p.Arg391Cys detected in one patient affected with spina bifida was also reported in one case of VWS2.…”

Section: Discussionmentioning

confidence: 99%

Rare deleterious variants in GRHL3 are associated with human spina bifida

et al. 2017

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Neural tube defects, including spina bifida, are among the most common birth defects caused by failure of neural tube closure during development. They have a complex etiology involving largely undetermined environmental and genetic factors. Previous studies in mouse models have implicated the transcription factor Grhl3 as an important factor in the pathogenesis of spina bifida. In the present study, we conducted a resequencing analysis of GRHL3 in a cohort of 233 familial and sporadic cases of spina bifida. We identified two novel truncating variants: one homozygous frameshift variant, p.Asp16Aspfs*10, in two affected siblings and one heterozygous intronic splicing variant, p.Ala318Glyfs*26. We also identified five missense variants, one of which was demonstrated to reduce the activation of gene targets in a luciferase reporter assay. With the previously identified p.Arg391Cys variant, eight variants were found in GRHL3. Comparison of the variant rate between our cohort and the ExAC database identified a significant enrichment of deleterious variants in GRHL3 in the whole gene and the transactivation region in spina bifida patients. These data provide strong evidence for a role of GRHL3 as a predisposing factor to spina bifida and will help dissect the complex etiology and pathogenic mechanisms of these malformations.

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“…This systematic approach has been previously applied to a number of complex phenotypes from autism spectrum disorders [19] to severe spermatogenic failure [20]. For NSOC, however, studies have been limited to either single genecentric analysis [21] of IRF6 or gene ontology (GO) enrichment analysis based on NSOC-associated genes [22] or those common between orofacial clefting and neural tube defects [23]. No attempt has therefore been made to expand the gene regulatory network based on multi-omics integrated systems analysis to identify causative genes explaining the missing heritability and in turn deliver more effective diagnosis in the form of targeted gene sequencing panels.…”

Section: Introductionmentioning

confidence: 99%

Systems genetics of nonsyndromic orofacial clefting provides insights into its complex aetiology

et al. 2018

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Nonsyndromic oral clefting (NSOC) is although one of the most common congenital disorders worldwide, its underlying molecular basis remains elusive. This process has been hindered by the overwhelmingly high level of heterogeneity observed. Given that hitherto multiple loci and genes have been associated with NSOC, and that complex diseases are usually polygenic and show a considerable level of missing heritability, we used a systems genetics approach to reconstruct the NSOC network by integrating human-based physical and regulatory interactome with whole-transcriptome microarray data. We show that the network component contains 53% (23/43) of the curated NSOC-implicated gene set and displays a highly significant propinquity (P < 0.0001) between genes implicated at the genomic level and those differentially expressed at the transcriptome level. In addition, we identified bona fide candidate genes based on topological features and dysregulation (e.g. ANGPTL4), and similarly prioritised genes at GWA loci (e.g. MYC and CREBBP), thus providing further insight into the underlying heterogeneity of NSOC. Gene ontology analysis results were consistent with the NSOC network being associated with embryonic organ morphogenesis and also hinted at an aetiological overlap between NSOC and cancer. We therefore recommend this approach to be applied to other heterogeneous complex diseases to not only provide a molecular framework to unify genes which may seem as disparate entities linked to the same disease, but to also predict and prioritise candidate genes for further validation, thus addressing the missing heritability.

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Shared molecular networks in orofacial and neural tube development

Cited by 21 publications

References 69 publications

Distinct blood DNA methylation profiles in subtypes of orofacial cleft

Distinct blood DNA methylation profiles in subtypes of orofacial cleft

Rare deleterious variants in GRHL3 are associated with human spina bifida

Systems genetics of nonsyndromic orofacial clefting provides insights into its complex aetiology

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