Molecular Screening of <i>VAX1</i> Gene Polymorphisms Uncovered the Genetic Heterogeneity of Non-Syndromic Orofacial Cleft in Saudi Arabian Patients

Objective: Nonsyndromic orofacial cleft (NSOFC) including cleft lip with or without cleft palate (CL±P) and cleft palate (CP) are multifactorial developmental disorders with both genetic and environmental etiological factors. In this study we investigated the association between CL±P and CP, and two polymorphisms previously determined using genome-wide association studies, as well as the association between consanguinity and CL±P and CP. Methods: DNA was extracted from saliva specimens from 171 triads consisting of affected individuals and their parents, as well as 189 control triads (matched for age, gender, and location) that were recruited from 11 referral hospitals in Saudi Arabia. Two polymorphisms, rs4752028 and rs7078160, located in the VAX1 gene were genotyped using real-time polymerase chain reaction. A transmission disequilibrium test was carried out using the Family-Based Association Test and PLINK (genetic tool-set) to measure the parent-of-origin effect. Results: Significant differences were found between affected individuals and the control group. In the case of the rs4752028 risk allele in cleft, the phenotypes were: CL±P (fathers: odds ratio [OR] 2.16 [95% CI 1.38–3.4]; mothers: OR 2.39 [95% CI 1.53–3.71]; and infants: OR 2.77 [95% CI 1.77–4.34]) and CP (fathers: OR 2.24 [95% CI 1.15–4.36] and infants: OR 2.43 [95% CI 1.25–4.7]). For CL±P and the rs7078160 risk allele, the phenotypes were: (fathers: OR 1.7 [95% CI 1.05–2.86]; mothers: OR 2.43 [95% CI 1.49–3.97]; and infants: OR 2.34 [95% CI 1.44–3.81]). In terms of consanguinity, we found significant association between consanguinity and the rs4752028 polymorphism minor allele among CL±P compared with controls (p = 0.001). Conclusion: This is the first study to find a relationship between these two loci on 10q25 (rs4752028 and rs7078160) and NSOFC in a population with high levels of consanguinity

Incidence of non-syndromic orofacial cleft during the COVID-19 pandemic in Saudi Arabia

Abstract Objectives This is the first national study to investigate the incidence of non-syndromic oro-facial clefts (NSOFC) and Pierre-Robin-Sequence in Saudi Arabia over the Covid-19 pandemic period. Methods All maternity hospitals (30-hospitals) in the major regions and cities of Saudi from November 2020-to-2021 were included in the study. Patients were evaluated for cleft phenotype using the LASHAL-classification system. The incidence of NSOFC in Saudi Arabia was calculated by comparing the number of NSOFCs cases born out of all live births during the study period at the included hospitals. Clinical examination was performed and information was gathered using a validated data collection form. Results In one year, 140,380 live-infants were born at the selected hospitals. Of these, 177 were diagnosed with NSOFC giving an incidence of 1.26/1,000 live-births in Saudi Arabia and the highest incidence in Medina city (2.46/1000 live-births). The incidence of cleft lip-and-palate (0.67/1000 live-births) was higher than that of cleft-palate (0.37/1000 live-births) and cleft-lip (0.22/1000 live-births). Pierre-Robin Sequence incidence was (0.04/1000 live-births). There were 21(12.1) or 23(13.2%) of NSOFC’s mothers exposed or vaccinated with Covid-19, respectively. Conclusion The national incidence of NSOFC in Saudi Arabia was 1.26/1000 live births with variation between phenotypes and regions in the country. In addition, to reporting Covid-19 infection prevalence and vaccine exposure among NSOFC's mothers, this study represents the first of its type to evaluate NSOFC prevalence in Saudi Arabia on a national level

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

Abstract 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

sj-docx-1-cpc-10.1177_10556656231224198 - Supplemental material for Maternal Exposure to Stress During Covid-19 and Non-Syndromic Orofacial Clefts: A Cohort Retrospective Study

Supplemental material, sj-docx-1-cpc-10.1177_10556656231224198 for Maternal Exposure to Stress During Covid-19 and Non-Syndromic Orofacial Clefts: A Cohort Retrospective Study by Heba Jafar Sabbagh, Mona Talal AlSharif, Fatma Dawood Abdulhameed, Aziza Johar Aljohar, Reema Mahdi Alhussain, Sultan Musaad Alghamdi, Najla Sulaiman Alrejaye, Latifa Yousef AlGudaibi, Bahaudbdin Ibraheem Sallout, Badi Shoaib Albaqawi, Eman Abdulbaset Alnamnakani, Lougin Khalid Brekeit, Osama Adel Basri, Manal Ibrahim Almalik, Norah Suliman Al Soqih, Ali Bakr Alshaikh, Abdullah Jameel Aburiziza, Faisal Ali Al Qahtani, Bushra Musaad Alghamdi, Asalah Khalid Alraddadi, Hadeel Hamza Khaja and Rana Abdullah Alamoudi in The Cleft Palate Craniofacial Journal</p

Additional file 1 of COVID-19 related risk factors and their association with non-syndromic orofacial clefts in five Arab countries: a case-control study

Supplementary Material

Environmental Risk Factors in the Etiology of Nonsyndromic Orofacial Clefts in the Western Region of Saudi Arabia

Objectives Nonsyndromic orofacial cleft (NSOFC) etiology is multifactorial and heterogeneous. This study aimed to identify environmental risk factors related to NSOFC in the Western Region of Saudi Arabia. Methods A case-control study carried out in seven hospitals in two main cities (Jeddah and Maddina) over 2 years on parents of 112 infants with NSOFC (infants were also examined) and 138 infant controls, matched for age (≤18 months), gender, and location, completed a questionnaire on 3-month pregestation and first trimester events. Results There was significantly increased NSOFC risk with twin pregnancies (P = .01, odds ratio [OR] = 9.5, 95% confidence interval [CI]: 1.15 to 78.4), maternal antibiotic use (P = .021, OR = 2.71, 95% CI: 1.11 to 6.62), antiemetic medication (P = .005, OR = 2.85, 95% CI: 1.3 to 6), severe morning sickness (P = .006, OR = 3.6, 95% CI: 1.34 to 9.65), illness (P = .009, OR = 2.19, 95% CI: 1.17 to 4.08), common cold/flu (P = .003, OR = 3.32, 95% CI: 1.48 to 7.58), Jorak smoking (P = .004, OR = 14.07, 95% CI: 1.55 to 128.1), and passive smoking (P = .05, OR = 2.05, 95% CI: 1.05 to 4.01). Reduced NSOFC risk was found with calcium supplementation (P = .02, OR = 0.32, 95% CI: 0.11 to 0.88), incense use (P = .03, OR = 0.58, 95% CI: 0.34 to 0.98), and maternal drinking water, with Zamzam water (which contains a high concentration of minerals) showing a significant protective effect compared with tap water (P = .01, 95% CI: 0.06 to 0.6) and bottled water (P = .02, 95% CI: 0.03 to 0.57). Conclusion Twin births, maternal antibiotic use, antiemetic medication, severe morning sickness, common cold/flu, Jorak smoking, and passive smoking were associated with infants born with NSOFC. Calcium supplementation, incense use, and Zamzam water reduced the risk of NSOFC, raising the possibility of community preventive programs