Genetics of nonsyndromic orofacial clefts

Abstract

With an average worldwide prevalence of approximately 1.2/1000 live births, orofacial clefts are the most common craniofacial birth defects in humans. Like other complex disorders, these birth defects are thought to result from the complex interplay of multiple genes and environmental factors. Significant progress in the identification of underlying genes and pathways has benefited from large populations available for study, increased international collaboration, rapid advances in genotyping technology, and major improvements in analytic approaches. Here we review recent advances in genetic epidemiological approaches to complex traits and their applications to studies of nonsyndromic orofacial clefts. Our main aim is to bring together a discussion of new and previously identified candidate genes to create a more cohesive picture of interacting pathways that shape the human craniofacial region. In future directions, we highlight the need to search for copy number variants that affect gene dosage and rare variants that are possibly associated with a higher disease penetrance. In addition, sequencing of protein-coding regions in candidate genes and screening for genetic variation in noncoding regulatory elements will help advance this important area of research.

Figure 1. Development of the orofacial structures

The medial nasal prominences enlarge and merge with each other during the 6^th–7^th weeks of gestation to form the intermaxillary segment providing the basis for both the philtrum and primary palate. The intermaxillary segment fuses with the flanking maxillary prominences giving rise to the upper lip. The lateral nasal prominences form the sides of the nose. The paired bilateral maxillary prominences form the upper jaw, and the paired mandibular prominences develop into the lower jaw. Adapted from (Helms et al., 2005).

Figure 2. Refining the isolated orofacial cleft phenotype for enhanced linkage analysis

Subclinical features (or ‘subphenotypes’) such as defects in the muscle that surrounds the mouth (Orbicularis Oris), dental anomalies, craniofacial morphology and speech-related disorders may be part of the overall spectrum of isolated clefting. Therefore, their inclusion in classic linkage approaches may boost the search for causal genetic variants. “Others?” in the figure refers to additional subphenotypes, such as variations in brain morphology; lip pits/prints, dermatoglyphic patterns, etc. A circle inside a pedigree symbol refers to an apparently ‘unaffected’ individual who harbors at least one of the subphenotypes and is therefore categorized as a potential gene-carrier; filled symbols refer to individuals with an overt cleft.