Peter A. Mossey

Cleft lip and palate

Clefts of the lip and palate are generally divided into two groups, isolated cleft palate and cleft lip with or without cleft palate, representing a heterogeneous group of disorders affecting the lips and oral cavity. These defects arise in about 1.7 per 1000 liveborn babies, with ethnic and geographic variation. Effects on speech, hearing, appearance, and psychology can lead to longlasting adverse outcomes for health and social integration. Typically, children with these disorders need multidisciplinary care from birth to adulthood and have higher morbidity and mortality throughout life than do unaffected individuals. This Seminar describes embryological developmental processes, epidemiology, known environmental and genetic risk factors, and their interaction. Although access to care has increased in recent years, especially in developing countries, quality of care still varies substantially. Prevention is the ultimate objective for clefts of the lip and palate, and a prerequisite of this aim is to elucidate causes of the disorders. Technological advances and international collaborations have yielded some successes.

Disruption of an AP-2α binding site in an IRF6 enhancer is associated with cleft lip

Previously we have shown that nonsyndromic cleft lip with or without cleft palate (NSCL/P) is strongly associated with SNPs in IRF6 (interferon regulatory factor 6). Here, we use multispecies sequence comparisons to identify a common SNP (rs642961, G>A) in a newly identified IRF6 enhancer. The A allele is significantly overtransmitted (P = 1 × 10−11) in families with NSCL/P, in particular those with cleft lip but not cleft palate. Further, there is a dosage effect of the A allele, with a relative risk for cleft lip of 1.68 for the AG genotype and 2.40 for the AA genotype. EMSA and ChIP assays demonstrate that the risk allele disrupts the binding site of transcription factor AP-2α and expression analysis in the mouse localizes the enhancer activity to craniofacial and limb structures. Our findings place IRF6 and AP-2α in the same developmental pathway and identify a high-frequency variant in a regulatory element contributing substantially to a common, complex disorder.

Key susceptibility locus for nonsyndromic cleft lip with or without cleft palate on chromosome 8q24.

We conducted a genome-wide association study involving 224 cases and 383 controls of Central European origin to identify susceptibility loci for nonsyndromic cleft lip with or without cleft palate (NSCL/P). A 640-kb region at chromosome 8q24.21 was found to contain multiple markers with highly significant evidence for association with the cleft phenotype, including three markers that reached genome-wide significance. The 640-kb cleft-associated region was saturated with 146 SNP markers and then analyzed in our entire NSCL/P sample of 462 unrelated cases and 954 controls. In the entire sample, the most significant SNP (rs987525) had a P value of 3.34 × 10−24. The odds ratio was 2.57 (95% CI = 2.02–3.26) for the heterozygous genotype and 6.05 (95% CI = 3.88–9.43) for the homozygous genotype. The calculated population attributable risk for this marker is 0.41, suggesting that this study has identified a major susceptibility locus for NSCL/P.

Genome-wide association study identifies two susceptibility loci for nonsyndromic cleft lip with or without cleft palate

We conducted a genome-wide association study for nonsyndromic cleft lip with or without cleft palate (NSCL/P) in 401 affected individuals and 1,323 controls, with replication in an independent sample of 793 NSCL/P triads. We report two new loci associated with NSCL/P at 17q22 (rs227731, combined P = 1.07 × 10−8, relative risk in homozygotes = 1.84, 95% CI 1.34–2.53) and 10q25.3 (rs7078160, combined P = 1.92 × 10−8, relative risk in homozygotes = 2.17, 95% CI 1.32–3.56).

Genome-wide meta-analyses of nonsyndromic cleft lip with or without cleft palate identify six new risk loci

We have conducted the first meta-analyses for nonsyndromic cleft lip with or without cleft palate (NSCL/P) using data from the two largest genome-wide association studies published to date. We confirmed associations with all previously identified loci and identified six additional susceptibility regions (1p36, 2p21, 3p11.1, 8q21.3, 13q31.1 and 15q22). Analysis of phenotypic variability identified the first specific genetic risk factor for NSCLP (nonsyndromic cleft lip plus palate) (rs8001641; PNSCLP = 6.51 × 10−11; homozygote relative risk = 2.41, 95% confidence interval (CI) 1.84–3.16).

Epidemiology of oral clefts 2012: an international perspective.

Classical descriptive epidemiology in the field of cleft lip and palate aims to quantify the problem, and in the higher income countries it is possible to do this with varying degrees of accuracy. This is not however possible in every country in the world, and epidemiology should seek to identify these data gaps with a view to improvement in the situation. Epidemiology must also be investigative and look for trends, associations and inter-population differences, with the aim of supporting aetiological research and advancing the translational agenda. This chapter is set out in three parts and seeks to address all three of the above areas. Birth defects in general and orofacial clefting in particular remain a relatively common and significant problem for not only the individual patients born with these defects in terms of death or disability, but also for their families and for society in general in terms of burden of care and health inequality. In high-income countries, despite very significant advances in treatment, problems in access to care and evidence base for cleft care still exist whereas in the developing world the consequences are lack of access to care and lack of infrastructure to help with quantification of the problem and consequently the ability to address it. The major questions in contemporary cleft lip and palate research surround ways of improving the evidence base for the treatment interventions used to optimise quality of care, and the ultimate scientific and humanitarian objective is primary prevention of those diseases and disorders that are preventable. Descriptive epidemiology underpins research enquiry in both of these major areas.

Global Economic Impact of Dental Diseases

Reporting the economic burden of oral diseases is important to evaluate the societal relevance of preventing and addressing oral diseases. In addition to treatment costs, there are indirect costs to consider, mainly in terms of productivity losses due to absenteeism from work. The purpose of the present study was to estimate the direct and indirect costs of dental diseases worldwide to approximate the global economic impact. Estimation of direct treatment costs was based on a systematic approach. For estimation of indirect costs, an approach suggested by the World Health Organization’s Commission on Macroeconomics and Health was employed, which factored in 2010 values of gross domestic product per capita as provided by the International Monetary Fund and oral burden of disease estimates from the 2010 Global Burden of Disease Study. Direct treatment costs due to dental diseases worldwide were estimated at US

Smoking and orofacial clefts: a United Kingdom-based case-control study.

298 billion yearly, corresponding to an average of 4.6% of global health expenditure. Indirect costs due to dental diseases worldwide amounted to US

Socioeconomic status and orofacial clefts in Scotland, 1989 to 1998.

144 billion yearly, corresponding to economic losses within the range of the 10 most frequent global causes of death. Within the limitations of currently available data sources and methodologies, these findings suggest that the global economic impact of dental diseases amounted to US

Addressing the challenges of cleft lip and palate research in India

442 billion in 2010. Improvements in population oral health may imply substantial economic benefits not only in terms of reduced treatment costs but also because of fewer productivity losses in the labor market.