Genes implicated in Cleft Lip Development

Cleft palate and cleft lip are some of the most common birth defects in the United States.  Many researchers have dedicated themselves to better understanding this phenomenon.  One interesting study is called, "Haploinsufficiency Leads to Cleft Lip and Palate" Science 22 September 2006: Vol. 313 no. 5794 p. 1751 by Fowzan S. Alkuraya, Irfan Saadi, Jennifer J. Lund, Annick Turbe-Doan, Cynthia C. Morton and Richard L. Maas.  Here is an excerpt: "Abstract - The posttranslational modification sumoylation can have multiple effects on its substrate proteins. We studied a patient with isolated cleft lip and palate and a balanced chromosomal translocation that disrupts the SUMO1 (small ubiquitin-related modifier) gene, resulting in haploinsufficiency. In mouse, we found that Sumo1 is expressed in the developing lip and palate and that a Sumo1 hypomorphic allele manifests an incompletely penetrant orofacial clefting phenotype. Products of several genes implicated in clefting are sumoylated, and the Sumo1 hypomorphic allele interacts genetically with a loss-of-function allele for one of these loci. Thus, sumoylation defines a network of genes important for palatogenesis."

Another interesting study is called, "Incidence of Cleft Lip and Palate and Risks of Additional Malformations" by Catharina Hagberg, D.D.S., Ph.D., Ola Larson, M.D., D.D.S., Ph.D., and Josef Milerad, M.D., Ph.D. The Cleft Palate-Craniofacial Journal: January 1998, Vol. 35, No. 1, pp. 40-45.  Here is an excerpt: "Abstract - Objective and Methods: Children with cleft lip and/or palate (n = 251) born between 1991 and 1995 in the county of Stockholm, Sweden, were studied with reference to incidence and rate ratios (RRs) of different types of clefts, gender, birth weight, mother's age, and length of pregnancy. Children who had clefts and additional malformations were compared with children who had clefts but no additional malformations.

Results: The incidence of clefts was 2.0/1000 live births, and it was higher among males than among females. The RR, an index of relative risk, was 1.58. The main groups, children with isolated cleft lip, children with cleft lip and palate, and children with isolated cleft palate, showed similar incidence values (0.6–0.7/1000 live births). Children with bilateral clefts had an incidence of 0.3/1000 live births. Additional malformations were found in approximately every sixth newborn with a cleft when children with Robin sequence were excluded. There was a tendency for newborns with bilateral clefts to have additional malformations (RR = 1.36; confidence interval = 0.74–2.49). Children with clefts and additional malformations had lower birth weight and were born earlier than children with clefts only.  Conclusion: Preterm cleft children with low birth weight should be screened for the presence of other birth defects."

Another interesting study is called, "Mode of inheritance of nonsyndromic cleft lip with or without cleft palate: a reanalysis." By L E Mitchell and N Risch - Division of Biostatistics, Washington University School of Medicine, St. Louis, MO 63110.  Am J Hum Genet. 1992 August; 51(2): 323–332.  Here is an excerpt: "Abstract - Nonsyndromic cleft lip with or without cleft palate (CL +/- P) is traditionally recognized as a multifactorial threshold trait (MFT). Recently, however, evidence for the involvement of a major gene in the etiology of CL +/- P has been reported. To assess the potential for major-gene involvement in the etiology of this trait, familial recurrence patterns from several family studies of CL +/- P were reanalyzed. The recurrence patterns in first-degree relatives of CL +/- P probands were found to be compatible with the expectations for either an MFT or a generalized single-major-locus (gSML) trait. The use of multiple thresholds based on proband sex, defect bilaterality, or palatal involvement did not help to discriminate between these models. However, the pattern of recurrence among MZ twins and more remote relatives of CL +/- P probands is not consistent with gSML inheritance but is compatible with either an MFT model or a model specifying multiple interacting loci. For such a model, no single locus can account for more than a sixfold increase in risk to first-degree relatives. These findings have important implications with regard to the feasibility of detecting linkage to loci conferring susceptibility to CL +/- P."

We all owe a debt of gratitude to these researchers for their fine work and dedication.  For more information, please read the studies in their entirety.