Gene Variations and the Risk of Cleft Lip or Cleft Palate

Jeffrey C. Murray, MD
University of Iowa
R01ES10876

Background: Clefts of the lip or palate are two of the most common birth defects. Clefts are complex in their causation resulting from both genetics and gene-environment interactions. The rate of occurrence of clefts varies across populations, but averages about one for every 700 live births. Clefts can result in the need for surgical procedures, speech therapy, psychological counseling, and dental and cosmetic interventions which can be quite costly and cause additional pain and suffering. Isolated clefts, those that occur in the absence of any other birth defect, account for about 70% of all cases of cleft lip and cleft palate.

Advance: Last year, these NIEHS-supported researchers reported that mutations in a specific gene, known as MSX1, account for more than 2% of all isolated clefts. To continue this line of research, they investigated the gene that encodes interferon regulatory factor 6 (IRF6) as a candidate gene because of its involvement in a cleft disorder known as Van der Woude's syndrome. In their current findings, they report that a single nucleotide polymorphism, a substitution of a single DNA building block, in the IRF6 gene is associated with isolated clefts and accounts for about 12% of all cases. Having this genetic variation tripled the risk of recurrence in families that already had one affected child. Added to the previous findings, these researchers report that they are now able to predict whether some parents are more likely than others to have a second child with an isolated cleft.

Implication: This study shows that DNA-sequence variations associated with the IRF6 gene are major contributors to cleft disorders. The results of this and the previous study show that the science has reached the point where it is possible to perform genetic testing to determine the risk of parents having a second child with a cleft lip or palate. The authors conclude that "[d]irect identification of genes can improve genetic counseling, assist in the identification of new genetic and environmental causes of syndromes, and provide options for treatment or prevention . . ."

Citation: Zucchero TM, Cooper ME, Maher BS, Daack-Hirsch S, Nepomuceno B, Ribeiro L, Caprau D, Christensen K, Suzuki Y, Machida J, Natsume N, Yoshiura K, Vieira AR, Orioli IM, Castilla EE, Moreno L, Arcos-Burgos M, Lidral AC, Field LL, Liu YE, Ray A, Goldstein TH, Schultz RE, Shi M, Johnson MK, Kondo S, Schutte BC, Marazita ML, Murray JC. Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate. N Engl J Med. 2004 Aug 19;351(8):769-80.