The complex genetics of cleft lip and palate

02_cjh055 22/1/04 11:23 am Page 7 European Journal of Orthodontics 26 (2004) 7–16 European Journal of Orthodontics vol. 26 no. 1  European Orthodontic Society 2004; all rights reserved. The complex genetics of cleft lip and palate Martyn T. Cobourne Division of Orthodontics and Craniofacial Development, GKT Dental Institute, London, UK Clefts of the lip and palate are a common craniofacial anomaly, requiring complex multidisciplinary treatment and having lifelong implications for affected individuals. The aetiology of both cleft lip with or without cleft palate (CLP) and isolated cleft palate (CP) is thought to be multifactorial, with both genetic and environmental factors playing a role. In recent years, a number of significant breakthroughs have occurred with respect to the genetics of these conditions, in particular, characterization of the underlying gene defects associated with several important clefting syndromes. These include the identification of mutations in the interferon regulatory factor-6 (IRF6) gene as the cause of van der Woude syndrome and the poliovirus receptor related-1 (PVRL1) gene as being responsible for an autosomal recessive ectodermal dysplasia syndrome associated with clefting. While no specific disease-causing gene mutations have been identified in non-syndromic clefting, a number of candidate genes have been isolated through both linkage and association studies. However, it is clear that environmental factors also play a role and an important area of future research will be to unravel interactions that occur between candidate genes and environmental factors during early development of the embryo. Orthodontists are intimately involved in the therapeutic management of individuals affected by CLP and it is important that they keep abreast of current knowledge of the aetiology behind these conditions. This review aims to summarize some of the more significant advances in the genetics of CLP and highlight current thinking on the modes of inheritance and genetic loci that might be involved in this complex disorder. SUMMARY Introduction Clefts involving the lip and/or palate (CLP) or isolated clefts of the palate (CP) are a significant congenital anomaly, requiring complex long-term treatment and having lifelong implications for those individuals unfortunate enough to be affected. They represent a complex phenotype and reflect a breakdown in the normal mechanisms involved during early embryological development of the face (Figure 1). The incidence of these defects varies according to geographical location, ethnicity and socio-economic status, but in Caucasian populations it is reasonably uniform, with 1:800 to 1:1000 (CLP) and approximately 1:1000 (CP) live births affected (Fraser, 1970; Bonaiti-Pellie et al., 1982; Gorlin et al., 2001). The clinical manifestations of these defects are diverse, ranging from isolated clefts of the lip to complete bilateral clefts of the lip, alveolus and palate (Figure 2). Broadly speaking, approximately 70 per cent of CLP cases are non-syndromic, occurring as an isolated condition unassociated with any other recognizable anomalies, while the remaining 30 per cent of syndromic cases are present in association with deficits or structural abnormalities occurring outside the region of the cleft (Jones, 1988; Schutte and Murray, 1999). Our understanding of the aetiology and pathogenesis of these conditions, particularly the non-syndromic variants, still remains relatively poor. This is a reflection of the complexity and diversity of the mechanisms involved at the molecular level during embryogenesis, with both genetic and environmental factors playing an important and influential role (Johnson and Bronsky, 1995; Schutte and Murray, 1999; Prescott et al., 2001; Spritz, 2001; Wilkie and Morriss-Kay, 2001; Murray, 2002). Primary evidence for a genetic role has been available for some years; the sibling risk for CLP is approximately 30 times higher than that for the normal population prevalence, while the concordance rate in monozygotic twins is approximately 25–45 per cent as opposed to 3–6 per cent for dizygotic twins (Mitchell and Risch, 1992; Gorlin et al., 2001). However, this lack of complete concordance in monozygotic twins also illustrates the importance of environmental factors in the aetiology of this condition. With recent advances in modern molecular biology and methods for the analysis of population genetics, progress has been made in identifying some of the genes associated with this anomaly and how they influence the embryonic development of the facial complex. This review aims to outline some of these mechanisms and highlight several key advances that have been made within this field over the last few years. Syndromic CLP Over 300 syndromes are known to have clefting of the lip or palate as an associated feature (Online Mendelian inheritance in man: http://www.ncbi.nlm.gov/omim). As with all clinically recognizable syndromes, cases of syndromic CLP or CP can be broadly subdivided into 02_cjh055 22/1/04 11:23 am Page 8 8 M . T. C O B O U R N E Figure 1 Embryological origins of the midline facial structures. (a, b) In the developing embryo, the lateral nasal processes form the alae and sides of the nose, while the medial nasal processes form the intermaxillary segment, composed of the upper lip philtrum, the primary palate and the four incisor teeth. The maxillary process forms the remainder of the upper lip and the secondary palate, consisting of the hard palate and associated dentition anteriorly and posteriorly, and the soft palate. Various types of orofacial clefting. (c) Unilateral cleft lip; (d) bilateral cleft lip; (e) unilateral cleft lip and primary palate; (f) bilateral cleft lip and primary palate; (g) complete unilateral cleft of the lip and palate; (h) complete bilateral cleft of the lip and palate; (i) isolated cleft of the secondary palate; (j) isolated cleft of the soft palate; (k) submucous cleft of the soft palate. those that occur as part of a characterized Mendelian disorder (resulting from a single gene defect), those arising from structural abnormalities of the chromosomes, syndromes associated with known teratogens or those whose causation remains obscure and are therefore currently uncharacterized. Single gene disorders are the result of specific gene mutations on the autosomes or sex chromosomes and are inherited following Mendelian rules (autosomal dominant or recessive and X-linked dominant or recessive, respectively) with varying levels of penetrance and expressivity. Cytogenetics, or the study of chromosomal abnormalities, has revealed a wide range of physical chromosomal alterations, including variations in both number and structure, which can cause perturbations of gene function and congenital malformations. It has been estimated that 6 per cent of all congenital malformations are due to visible cytogenetic abnormalities (Kalter and Warkany, 1983) and approximatel (...truncated)