Our laboratory has been involved in studying the genetics of cleft lip and palate (CL/P) for over two decades and Dr. Murray has collaborators worldwide.
Clefts of the lip and/or palate (CL/P) are common birth defects. These birth defects require surgical, nutritional, dental, speech, medical and behavioral interventions and impose a substantial economic and societal burden. CL/P affects about 1 in 700 births with wide variability across geographic origin and socioeconomic status. In general, Asian or Amerindian populations have the highest birth prevalence, often as high as 1 in 500, with European derived populations intermediate at about 1 in 1000, and African-derived populations the lowest at 1 in 2500. CL/P has remarkable differences in frequency by sex and side of clefting. There is a 2:1 male to female ratio and a similar 2:1 left-side:right-side ratio for unilateral lip clefts.
CL/P can occur on their own as an isolated birth defect (non-syndromic) or as part of a syndrome with other birth defects. In isolated clefts, affected individuals have no other physical or developmental anomalies. Most studies suggest that about 70% of cases of CL/P and 50% of cases of cleft palate only (CPO) are non-syndromic. The remaining 30% of cases are syndromic, meaning that the individual with a cleft also has other physical and/or developmental anomalies. The syndromic cases can be subdivided into more than 500 Mendelian disorders, cases due to chromosome anomalies, teratogens, and uncategorized syndromes. Among isolated clefts, the environment also plays a substantial role, with maternal smoking during pregnancy a well-established risk factor.
The complex etiology of clefting affords opportunities to identify gene-gene or gene-environment interactions that can shed light on human embryology and its disturbances. Recently, it has become practical to identify genes and/or environmental contributors to complex traits such as CLP by using a combination of epidemiology, family collections, careful phenotyping including high resolution imaging, high throughput genotyping, robust statistical strategies, comprehensive studies of gene expression and epigenetics, and by characterizing animal models. Identification of genes can be carried out: (1) using linkage methods with large families, smaller but inbred families, or affected relative pairs, (2) using association approaches with nuclear families, trios or case control samples, or (3) by direct medical resequencing. Each of these has its own advantages and disadvantages dependent on the underlying genetic architecture of the disease as well as realities of economy and technology. Advances in high throughput genotyping (including copy number variants), a detailed Hapmap of the human genome and progress in analytic approaches have all made the genome wide association approach (GWAS) practical although challenges remain.
In one example of syndromic clefting, Van der Woude syndrome, we have identified the gene (IRF6) in collaboration with Brian Schutte and are now applying this finding to study the role of IRF6 (Kondo et al 2003, Zucchero et al 2004, Rahimov et al 2008) in facial development. Our laboratory has also identified by linkage and positional mapping a highly significant association between FOXE1 and orofacial clefts (Moreno et al 2009).
We hope that our research will help to characterize etiologic genes as well as gene-gene and gene-environmental interactions related to CL/P. Our findings will provide a resource for long-term studies in mouse and other animal models to better understand the embryonic development of these birth defects. The genetic findings will also aid in developing projects on micronutrient intervention trials to prevent cleft lip and palate. The outcome of this will be immediate and direct contributions to genetic counseling, prevention of these birth defects, and a far better understanding of the basic biology of craniofacial development. We hope that the research we are conducting will confirm that complex human birth defects can be understood and that diagnosis and prevention of such birth defects can be improved.