Identification of Causative Variants Contributing to Nonsyndromic Orofacial Clefts Using Whole-Exome Sequencing in a Saudi Family

Mahdi, Hadiah Bassam Al; Edris, Sherif; Bahieldin, Ahmed; Al‐Aama, Jumana Y.; Elango, Ramu; Jamalalail, Bassam Adnan; Sabbagh, Heba Jafar

doi:10.1089/gtmb.2019.0233

Cited by 9 publications

(8 citation statements)

References 23 publications

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“…Many factors contribute to NSOFC including genetics [ 6 – 9 ], which plays a main role in the development of NSOFC, environmental, and stress-environmental interaction risk factors [ 10 ]. The interaction of these factors and their relation with NSOFC etiology is complex.…”

Section: Introductionmentioning

confidence: 99%

COVID-19 related risk factors and their association with non-syndromic orofacial clefts in five Arab countries: a case-control study

et al. 2023

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Background The environmental etiology of non-syndromic orofacial clefts (NSOFCs) is still under research. The aim of this case-control study is to assess COVID-19 associated factors that may be related to the risk of NSOFC in five Arab countries. These factors include COVID-19 infection, COVID-19 symptoms, family member or friends infected with COVID-19, stress, smoking, socioeconomic status and fear of COVID-19. Methods The study took place in governmental hospitals in five Arab countries from November 2020 to November 2021. Controls are matched in the month of delivery and site of recruitment. A clinical examination was carried out using LASHAL classification. Maternal exposure to medication, illnesses, supplementation, COVID-19 infection during their pregestation and 1st trimester periods were evaluated using a validated questionnaire. Maternal exposure to stress was assessed using the Life Events scale, fear of covid-19 scale, family member or friend affected with covid-19 infection, pregnancy planning and threatened abortion. Results The study recruited 1135 infants (386 NSOFC and 749 controls). Living in urban areas, maternal exposure to medications 3-months pregestation, maternal exposure to any of the prenatal life events and maternal fear of COVID-19 significantly increased the risk of having a child with NSOFC. On the other hand, mothers exposed to supplementation 3-months pregestation, mothers suspected of having COVID-19 infection, family members or friends testing positive with COVID-19 significantly decreased the risk of having a child with NSOFC. Conclusions This study suggests that NSOFC may be associated with maternal exposure to lifetime stress and COVID-19 fear in particular, with no direct effect of the COVID-19 infection itself. This highlights the importance of providing psychological support for expecting mothers during stressful events that affect populations such as the COVID-19 pandemic, in addition to the usual antenatal care.

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Section: Introductionmentioning

confidence: 99%

COVID-19 related risk factors and their association with non-syndromic orofacial clefts in five Arab countries: a case-control study

et al. 2023

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“…Common variants analysis through genome-wide association studies have identified a number of risk variants associated with nsCL±P [6][7][8][9][10][11] . The role of rare coding mutations in the etiology of this birth defect have also been reported [12][13][14] . However, ~75% of the genetic heritability of this nsOFCs remain unknown.…”

Section: Introductionmentioning

confidence: 91%

“…Common variant analysis through genome-wide association studies has identified a number of risk variants associated with nsCL ± P. [6][7][8][9][10][11] The role of rare coding mutations in the etiology of this birth defect has also been reported. [12][13][14] However, ∼75% of the genetic heritability of these nsOFCs remain unknown. Whole-genome sequencing (WGS) is a powerful sequencing strategy that provides the opportunity to identify novel/rare variants present across the entire genome.…”

Section: Introductionmentioning

confidence: 99%

Damaging Mutations in AFDN Contribute to Risk of Nonsyndromic Cleft Lip With or Without Cleft Palate

Awotoye

Mossey

Hetmanski

et al. 2022

The Cleft Palate Craniofacial Journal

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Novel or rare damaging mutations have been implicated in the developmental pathogenesis of nonsyndromic cleft lip with or without cleft palate (nsCL ± P). Thus, we investigated the human genome for high-impact mutations that could explain the risk of nsCL ± P in our cohorts. We conducted next-generation sequencing (NGS) analysis of 130 nsCL ± P case-parent African trios to identify pathogenic variants that contribute to the risk of clefting. We replicated this analysis using whole-exome sequence data from a Brazilian nsCL ± P cohort. Computational analyses were then used to predict the mechanism by which these variants could result in increased risks for nsCL ± P. We discovered damaging mutations within the AFDN gene, a cell adhesion molecule (CAMs) that was previously shown to contribute to cleft palate in mice. These mutations include p.Met1164Ile, p.Thr453Asn, p.Pro1638Ala, p.Arg669Gln, p.Ala1717Val, and p.Arg1596His. We also discovered a novel splicing p.Leu1588Leu mutation in this protein. Computational analysis suggests that these amino acid changes affect the interactions with other cleft-associated genes including nectins (PVRL1, PVRL2, PVRL3, and PVRL4) CDH1, CTNNA1, and CTNND1. This is the first report on the contribution of AFDN to the risk for nsCL ± P in humans. AFDN encodes AFADIN, an important CAM that forms calcium-independent complexes with nectins 1 and 4 (encoded by the genes PVRL1 and PVRL4). This discovery shows the power of NGS analysis of multiethnic cleft samples in combination with a computational approach in the understanding of the pathogenesis of nsCL ± P.

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“…Despite extensive genome-wide association studies (GWAS) which have identi ed about 60 common risk loci, ~75% of the estimated heritability of liability to nsCL/P remains unexplained [8][9][10][11][12][13] . The contribution of rare coding variants has also been investigated to identify this missing heritability [14][15][16] .…”

Section: Introductionmentioning

confidence: 99%

Whole-genome Sequencing Reveals De-novo Mutations Associated with Nonsyndromic Cleft Lip/Palate

Awotoye

Mossey

Hetmanski

et al. 2021

Preprint

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The majority (85%) of nonsyndromic cleft lip with or without cleft palate (nsCL/P) cases occur sporadically, suggesting a role for de novo mutations (DNMs) in the etiology of nsCL/P. To identify high impact DNMs that contribute to the risk of nsCL/P, we conducted whole genome sequencing (WGS) analyses in 130 African case-parent trios (affected probands and unaffected parents). We identified 162 high confidence protein-altering DNMs that contribute to the risk of nsCL/P. These include novel loss-of-function DNMs in the ACTL6A, ARHGAP10, MINK1, TMEM5 and TTN genes; as well as missense variants in ACAN, DHRS3, DLX6, EPHB2, FKBP10, KMT2D, RECQL4, SEMA3C, SEMA4D, SHH, TP63, and TULP4. Experimental evidence showed that ACAN, DHRS3, DLX6, EPHB2, FKBP10, KMT2D, MINK1, RECQL4, SEMA3C, SEMA4D, SHH, TP63, and TTN genes contribute to facial development and mutations in these genes could contribute to CL/P. Association studies have identified TULP4 as a potential cleft candidate gene, while ARHGAP10 interacts with CTNNB1 to control WNT signaling. DLX6, EPHB2, SEMA3C and SEMA4D harbor novel damaging DNMs that may affect their role in neural crest migration and palatal development. This discovery of pathogenic DNMs also confirms the power of WGS analysis of trios in the discovery of potential pathogenic variants.

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Identification of Causative Variants Contributing to Nonsyndromic Orofacial Clefts Using Whole-Exome Sequencing in a Saudi Family

Cited by 9 publications

References 23 publications

COVID-19 related risk factors and their association with non-syndromic orofacial clefts in five Arab countries: a case-control study

COVID-19 related risk factors and their association with non-syndromic orofacial clefts in five Arab countries: a case-control study

Damaging Mutations in AFDN Contribute to Risk of Nonsyndromic Cleft Lip With or Without Cleft Palate

Whole-genome Sequencing Reveals De-novo Mutations Associated with Nonsyndromic Cleft Lip/Palate

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