Rare deleterious variants in <i>GRHL3</i>
 are associated with human spina bifida

Lemay, Philippe; Marco, Patrizia De; Emond, Alexandre; Spiegelman, Dan; Dionne‐Laporte, Alexandre; Laurent, Sandra B.; Merello, Elisa; Accogli, Andrea; Rouleau, Guy A.; Capra, Valeria; Kibar, Zoha

doi:10.1002/humu.23214

Cited by 31 publications

(28 citation statements)

References 34 publications

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“…This variant leads to an arginine-to-cysteine substitution (NP_002327.2: p.Arg391Cys) in an evolutionarily conserved DNA-binding domain (figure 5). This change has been reported as a de novo variant in two patients, one with a CLP and lip pits,22 the other with spina bifida 2322 24…”

Section: Resultsmentioning

confidence: 82%

Whole exome sequencing identifies mutations in 10% of patients with familial non-syndromic cleft lip and/or palate in genes mutated in well-known syndromes

Basha¹,

Demeer²,

Revençu³

et al. 2018

J Med Genet

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These data demonstrate that patients with CL/P without cardinal signs of a syndrome may still carry a mutation in a gene linked to syCL/P. Rare coding and non-coding variants in syCL/P genes could in part explain the controversial question of 'missing heritability' for nsCL/P. Therefore, gene panels designed for diagnostic testing of syCL/P should be used for patients with nsCL/P, especially when there is at least third-degree family history. This would allow a more precise management, follow-up and genetic counselling. Moreover, stratified cohorts would allow hunting for genetic modifiers.

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Section: Resultsmentioning

confidence: 82%

Whole exome sequencing identifies mutations in 10% of patients with familial non-syndromic cleft lip and/or palate in genes mutated in well-known syndromes

Basha¹,

Demeer²,

Revençu³

et al. 2018

J Med Genet

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“…In a previous study, the occurrence of NTDs in curly tail mice and knockout mice showed the full penetrance of spina bifida, which suggested Grhl3 as a candidate gene for NTDs (Gustavsson et al, ). In humans, a study found several rare variants of GRHL3 in 233 familial and sporadic spina bifida patients in an Italian population (Lemay et al, ). In our study, we found that rs2486668 increased the risk for spinal and encephalic NTDs in a Chinese population.…”

Section: Discussionmentioning

confidence: 99%

“…Overall, evidence from animals has demonstrated that the Grhl3 gene is essential for spinal neurulation (De Castro, Hirst, et al, ). A population study conducted using a whole‐exome sequencing (WES) method in 233 Italian cases of spina bifida found two novel truncating variants and five rare missense variants of GRHL3 (Lemay et al, ). However, the role of GRHL3 in human NTDs has only been explored for spina bifida subtype, and the associations between genetic variants and other phenotypes in human populations need to be examined.…”

Section: Introductionmentioning

confidence: 99%

Genetic variants in GRHL3 and risk for neural tube defects: A case–control and case–parent triad/control study

Yang

Xiao

Tian

et al. 2019

Birth Defects Research

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Background: Neural tube defects (NTDs) are the most common severe birth defects with complex etiologies. Previous studies conducted on animals have suggested that the Grhl3 gene is essential for closure of the spinal neural tube, but little evidence from human studies on the variants of GRHL3 gene has been provided, especially the common genetic variants. Methods: To investigate the relationship between common genetic variants of GRHL3 and the risk for NTDs, we performed a case-control study and a caseparent triad/control study. Fast-target enrichment sequencing was performed to screen exon regions from 503 NTD cases, and three tag SNPs (single nucleotide polymorphisms, including rs12030057, rs2486668, and rs545809) were selected according to the sequencing results. Then, Sequenom MassARRAY genotyping was performed in 757 case parents and 519 controls to obtain genotype information of the target variant sites among all NTD triads and controls. Results: The genotype distributions of all SNPs were in accordance with Hardy-Weinberg Equilibrium (HWE) in the control population. In the case-control study, significant associations were found between C27G genetic variants on rs2486668 and risk for spina bifida and encephalocele, respectively, under different genetic models.Consistently, in the case-parent triad/control study, GG genotype on rs2486668 was associated with increased risk for spina bifida, with a RR of 2.15 (95% CI:1.20-3.83). However, no parent-of-origin effect was found for any tag SNPs. Conclusion: The GRHL3 C67G missense variant may increase the risk for spina bifida and encephalocele phenotypes. K E Y W O R D Scase-parent triads, common variants, grainyhead like transcription factor 3, neural tube defects, single nucleotide polymorphisms

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“…Therefore, our group has previously conducted whole exome sequencing (WES) in 43 trios affected with severe forms of NTDs (mainly MMC and anencephaly) and identified an important role for de novo variants in their etiology. We also previously used WES in three families each with two MMC cases as well as molecular inversion probe sequencing in a larger cohort, and we demonstrated a strong implication of GRHL3 (Grainyhead Like Transcription Factor 3; OMIM *608317) in the etiology of MMC (Lemay et al., ; Lemay et al, ). In our previous WES studies, we aimed at investigating the role of highly deleterious variants, defined as frameshift, stop, or splicing variants, in the causation of open and severe NTD (mainly MMC).…”

Section: Introductionmentioning

confidence: 99%

“…In our previous WES studies, we aimed at investigating the role of highly deleterious variants, defined as frameshift, stop, or splicing variants, in the causation of open and severe NTD (mainly MMC). In this study, we conducted WES in five new families affected with both forms of open and closed NTDs and we reassessed the previously published cohorts consisting mainly of open MMC (Lemay et al., ; Lemay et al, ). WES data were analyzed using a biased candidate gene approach and an unbiased genetic burden approach.…”

Section: Introductionmentioning

confidence: 99%

Whole exome sequencing identifies novel predisposing genes in neural tube defects

Lemay

Marco

Traverso

et al. 2018

Molec Gen & Gen Med

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Background Neural tube defects (NTD) are among the most common defects affecting 1:1000 births. They are caused by a failure of neural tube closure during development. Their clinical presentation is diverse and dependent on the site and severity of the original defect on the embryonic axis. The etiology of NTD is multifactorial involving environmental factors and genetic variants that remain largely unknown. Methods We have conducted a whole exome sequencing (WES) study in five new NTD families and pooled the results with WES data from three NTD families and 43 trios that were previously investigated by our group. We analyzed the data using biased candidate gene and unbiased gene burden approaches. Results We identified four novel loss‐of‐function variants in three genes, MTHFR, DLC1, and ITGB1, previously associated with NTD. Notably, DLC1 carried two protein truncating variants in two independent cases. We also demonstrated an enrichment of variants in MYO1E involved in cytoskeletal remodeling. This enrichment reached borderline significance in a replication cohort supporting the association of this new candidate gene to NTD. Conclusion These data provide some key insights into the pathogenic mechanisms of human NTD and demonstrate the power of next‐generation sequencing in deciphering the genetics of this complex trait.

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Rare deleterious variants in GRHL3 are associated with human spina bifida

Cited by 31 publications

References 34 publications

Whole exome sequencing identifies mutations in 10% of patients with familial non-syndromic cleft lip and/or palate in genes mutated in well-known syndromes

Whole exome sequencing identifies mutations in 10% of patients with familial non-syndromic cleft lip and/or palate in genes mutated in well-known syndromes

Genetic variants in GRHL3 and risk for neural tube defects: A case–control and case–parent triad/control study

Whole exome sequencing identifies novel predisposing genes in neural tube defects

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