No abstract

Ciliopathies are pleiotropic human diseases resulting from defects of the primary cilium, and these patients often have cleft lip and palate. IFT88 is required for the assembly and function of the primary cilia, which mediate the activity of key developmental signaling pathways. Through whole exome sequencing of a family of three affected siblings with isolated cleft lip and palate, we discovered that they share a novel missense mutation in IFT88 (c.915G > C, p.E305D), suggesting this gene should be considered a candidate for isolated orofacial clefting. In order to evaluate the function of IFT88 in regulating craniofacial development, we generated Wnt1-Cre;Ift88fl/fl mice to eliminate Ift88 specifically in cranial neural crest (CNC) cells. Wnt1-Cre;Ift88fl/flpups died at birth due to severe craniofacial defects including bilateral cleft lip and palate and tongue agenesis, following the loss of the primary cilia in the CNC-derived palatal mesenchyme. Loss of Ift88 also resulted in a decrease in neural crest cell proliferation during early stages of palatogenesis as well as a downregulation of the Shh signaling pathway in the palatal mesenchyme. Importantly, Osr2KI-Cre;Ift88fl/flmice, in which Ift88 is lost specifically in the palatal mesenchyme, exhibit isolated cleft palate. Taken together, our results demonstrate that IFT88 has a highly conserved function within the primary cilia of the CNC-derived mesenchyme in the lip and palate region in mice and is a strong candidate as an orofacial clefting gene in humans.

BackgroundSeveral lifestyle and environmental exposures have been suspected as risk factors for oral clefts, although few have been convincingly demonstrated. Studies across global diverse populations could offer additional insight given varying types and levels of exposures.MethodsWe performed an international case–control study in the Democratic Republic of the Congo (133 cases, 301 controls), Vietnam (75 cases, 158 controls), the Philippines (102 cases, 152 controls), and Honduras (120 cases, 143 controls). Mothers were recruited from hospitals and their exposures were collected from interviewer‐administered questionnaires. We used logistic regression modeling to estimate odds ratios (OR) and 95% confidence intervals (CI).ResultsFamily history of clefts was strongly associated with increased risk (maternal: OR = 4.7; 95% CI, 3.0–7.2; paternal: OR = 10.5; 95% CI, 5.9–18.8; siblings: OR = 5.3; 95% CI, 1.4–19.9). Advanced maternal age (5 year OR = 1.2; 95% CI, 1.0–1.3), pregestational hypertension (OR = 2.6; 95% CI, 1.3–5.1), and gestational seizures (OR = 2.9; 95% CI, 1.1–7.4) were statistically significant risk factors. Lower maternal (secondary school OR = 1.6; 95% CI, 1.2–2.2; primary school OR = 2.4, 95% CI, 1.6–2.8) and paternal education (OR = 1.9; 95% CI, 1.4–2.5; and OR = 1.8; 95% CI, 1.1–2.9, respectively) and paternal tobacco smoking (OR = 1.5, 95% CI, 1.1–1.9) were associated with an increased risk. No other significant associations between maternal and paternal factors were found; some environmental factors including rural residency, indoor cooking with wood, chemicals and water source appeared to be associated with an increased risk in adjusted models.ConclusionOur study represents one of the first international studies investigating risk factors for clefts among multiethnic underserved populations. Our findings suggest a multifactorial etiology including both maternal and paternal factors. Birth Defects Research (Part A) 103:863–879, 2015. © 2015 The Authors Birth Defects Research Part A: Clinical and Molecular Teratology Published by Wiley Periodicals, Inc.

While several studies have investigated maternal exposures as risk factors for oral clefts, few have examined paternal factors. We conducted an international multi-centered case–control study to better understand paternal risk exposures for oral clefts (cases = 392 and controls = 234). Participants were recruited from local hospitals and oral cleft repair surgical missions in Vietnam, the Philippines, Honduras, and Morocco. Questionnaires were administered to fathers and mothers separately to elicit risk factor and family history data. Associations between paternal exposures and risk of clefts were assessed using logistic regression adjusting for potential confounders. A father’s personal/family history of clefts was associated with significantly increased risk (adjusted OR: 4.77; 95% CI: 2.41–9.45). No other significant associations were identified for other suspected risk factors, including education (none/primary school v. university adjusted OR: 1.29; 95% CI: 0.74–2.24), advanced paternal age (5-year adjusted OR: 0.98; 95% CI: 0.84–1.16), or pre-pregnancy tobacco use (adjusted OR: 0.96; 95% CI: 0.67–1.37). Although sample size was limited, significantly decreased risks were observed for fathers with selected occupations. Further research is needed to investigate paternal environmental exposures as cleft risk factors.

Background Cleft is one of the most common birth defects globally and the lack of access to surgery means millions are living untreated. Smoke exposure from cooking occurs infrequently in developed countries but represents a high-proportion of smoke exposure in less-developed regions. We aimed to study if smoke exposure from cooking is associated with an increased risk in cleft, while accounting for other smoke sources. Methods We conducted a population-sampled case-control study of children with cleft lip and/or palate and healthy newborns from Vietnam, Philippines, Honduras, Nicaragua, Morocco, Congo, and Madagascar. Multivariable regression models were used to assess associations between maternal cooking during pregnancy, parental smoking, and household tobacco smoke with cleft. Results 2137 cases and 2014 controls recruited between 2012-2017 were included. While maternal smoking was uncommon (<1%), 58.3% case and 36.1% control mothers cooked over an open fire inside. Children whose mothers reported cook smoke exposure were 49% (95% confidence interval (CI) = 1.2-1.8) more likely to have a child with a cleft. This was consistent in five of seven countries. No significant associations were found for any other smoke exposure. Conclusions Our finding of maternal cook smoke and cleft in low-resource countries, similar to maternal tobacco smoke in high-resource countries, may reflect a common etiology. This relationship was present across geographically diverse countries with variable socioeconomic statuses and access to care. Exposures specific to low-resource settings must be considered to develop public health strategies that address the populations at increased risk of living with cleft and inform the mechanisms leading to cleft development.