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Cleft lip and palate: understanding genetic and environmental influences

Subjects

Key Points

  • Clefts of the lip and/or palate (CLP) are common birth defects of complex aetiology. CLP affects approximately 1 in 700 live births, with wide variability across geographic origin, racial and ethnic groups, as well as environmental exposures and socioeconomic status.

  • CLP can occur in syndromic or non-syndromic forms. This Review focuses on the latter.

  • Although twin studies and familial clustering studies have provided compelling evidence for a genetic component to non-syndromic CLP, few pedigrees show clear-cut Mendelian inheritance and many cases appear to be sporadic.

  • Accurate phenotyping is crucial to understanding both the epidemiology and aetiology of any congenital malformation because the power to detect effects is weakened when heterogeneous groups are treated as a single entity.

  • To date, genetic approaches to non-syndromic CLP have included: linkage analysis using large, multiplex families or smaller but inbred families, or analysis of affected relative pairs; association studies using case–parent trios or case–control samples; identification of chromosomal anomalies or micro-deletions in cases; and direct sequencing of affected individuals. Genome-wide association studies have provided recent major advances in our understanding of genes and pathways that have a role in the aetiology of CLP. There is remarkable heterogeneity by ancestry in the relative contributions by genes found with common variants contributing to CLP.

  • There is evidence that environmental factors have a role in CLP risk and interactions of the environment with certain genetic variants have been identified.

  • The next critical phase of statistical analyses will be to examine the heterogeneity underlying the aetiology of oral clefts and to investigate the gene–gene and gene–environment interactions that control risk. Integration of genetic and environmental risk using epigenetics, systems biology, gene expression and epidemiology will be required to generate a synthesis that will both better characterize aetiologies and eventually lead to improvements in prevention and clinical care.

Abstract

Clefts of the lip and/or palate (CLP) are common birth defects of complex aetiology. CLP can occur in isolation or as part of a broad range of chromosomal, Mendelian or teratogenic syndromes. Although there has been marked progress in identifying genetic and environmental triggers for syndromic CLP, the aetiology of the more common non-syndromic (isolated) forms remains poorly characterized. Recently, using a combination of epidemiology, careful phenotyping, genome-wide association studies and analysis of animal models, several distinct genetic and environmental risk factors have been identified and confirmed for non-syndromic CLP. These findings have advanced our understanding of developmental biology and created new opportunities for clinical translational research.

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Figure 1: Development of the lip and palate.
Figure 2: Types of cleft.
Figure 3: Subclinical phenotypes.

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Acknowledgements

We should like to thank many colleagues who have collaborated with us over the years and in particular K. Christensen, R. Lie, A. Jugessur, A. Lidral, J. Hecht, A. Vieira, M. Shi, P. Jezewski, D. Fitzpatrick, R. Munger, P. Trainor, J. Dixon, P. Romitti, P. Nopoulos, J. Canady, B. Schutte, K. Buetow, A. Sander, G. Wehby, S. Daack-Hirsch and S. Weinberg, as well as many students. We apologize for being unable to cite all of the relevant papers. We gratefully acknowledge generous funding sources including the Medical Research Council (G0901539), Wellcome Trust (082,868), US National Institutes of Health (P50-DE016215, R01-DE08559, R01-DE016148, R01-DE014581, U01-DE018993 and U01-DE20057), the Healing Foundation and the Manchester NIHR Biomedical Research Centre.

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Correspondence to Jeffrey C. Murray.

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Supplementary information

Supplementary information S1 (table)

Clefting syndromes in which the mutated gene has been identified (PDF 251 kb)

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COGENE

EMAGE database of in situ gene expression patterns in the mouse embryo

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Online Mendelian Inheritance in Man (OMIM)

SUPPLEMENTARY INFORMATION

S1 (table)

Glossary

Nares

The nostrils or nasal passages

Primary palate

The anterior portion of the palate including the bony component in humans.

Secondary palate

Posterior or soft palate in humans.

Multiplex family

A family in which multiple members are affected by an inherited disease.

Lip pit

An indentation and/or sinus tract in the lower lip that is usually located to one or both sides of the midline. Lip prints are visual impressions taken of the upper and lower lip that can indicate the presence of pits.

Orbicularis oris

The muscle surrounding the mouth.

Velopharyngeal insufficiency

Incomplete closing of the velopharyngeal sphincter (soft palate muscle) during speech.

Oral periderm

A superficial layer of flattened cells which develops from the single-cell-layered ectoderm to form a transient covering for the oral epithelia.

Odds ratio

A measurement of association that is commonly used in case–control studies. It is defined as the odds of exposure to the susceptible genetic variant in individuals with disease compared with that in controls. If the odds ratio is significantly greater than one, the genetic variant is associated with the disease.

Mendelian randomization

The random assignment of alleles from parents to offspring that occurs during gamete formation. It is the underlying concept of a method to genetically stratify individuals in a large population sample and then to evaluate phenotypic differences based on a pre-specified genotype.

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Dixon, M., Marazita, M., Beaty, T. et al. Cleft lip and palate: understanding genetic and environmental influences. Nat Rev Genet 12, 167–178 (2011). https://doi.org/10.1038/nrg2933

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