Jacqueline T. Hecht, PhD, Professor of Pediatrics, University of Texas Medical School at Houston

What is the cause of my child’s cleft lip and palate? This question is frequently asked by parents. Usually they are told that the cause cannot be determined for their child. The textbook explanation is that cleft lip is caused by a complex interaction of genes and the environment. Research in this field has begun to accelerate since the mapping of the human genome.

The following article is an update on the genetics of cleft lip and palate written by Dr. Jacqueline Hecht, a well-known geneticist-researcher at the University of Texas. Many of the families in the Cleft Lip/Palate Program at Boston Children’s Hospital have participated in her ongoing studies by contributing blood samples.

Cleft lip with or without cleft palate is a common birth defect found in more than 200 recognizable syndromes, but more often as an isolated birth defect, called nonsyndromic cleft lip with or without cleft palate (NSCLP). NSCLP occurs in 1/1,000 Caucasian live births with males affected twice as frequently as females. A similar birth prevalence of NSCLP has been reported in the Hispanic population but is less frequent among African-American live births. NSCLP affects approximately 4,000 newborns/year in the U.S. and has a significant impact on the health care of these children. While surgical techniques have improved facial repair, NSCLP is associated with medical and social consequences.

The cause of NSCLP is complex, involving numerous genetic and environmental factors. Large population studies of NSCLP families suggest that genetic factors play a crucial role but the identification of responsible genes has been a difficult task. NSCLP most often occurs as an isolated defect in families without any history of clefting. However, in a subset of cases, NSCLP recurs in family members but does not follow a specific pattern of inheritance. Large population studies of NSCLP families suggest that genetic factors play a crucial role. Using multiplex NSCLP families (families with multiple members affected with NSCLP) and isolated NSCLP cases (families with a single affected individual), a number of susceptibility genes have been identified including TGFA, BCL3, MSX1, TGFB3 and RARA. These genes have been studied in a variety of populations but none of these genes have been shown to play a major role in causing NSCLP.

We have assembled two patient populations with NSCLP, multiplex NSCLP families and simplex trios in which the child is the only affected. Previous and continuing work primarily focused on the multiplex NSCLP families, as these families appear to have a higher genetic predisposition for NSCLP. A large number of families is required to track down the gene, or more likely the genes, responsible for NSCLP. We are now actively expanding our family set to include at least 150 families. This is a challenge as the multiplex families are rare and scattered throughout the United States. Nevertheless, we have successfully collected more than 75 families. This has been accomplished through collaborations with Dr. John Mulliken at Boston Children’s Hospital, Dr. Sam Stal at Texas Children’s Hospital and the University of Texas Cranio-facial Clinic. Individuals with NSCLP and their families are evaluated and characterized to ensure that they have NSCLP and not a syndrome associated with clefting. Blood samples are obtained from family members after informed consent and DNA is prepared from the samples. Blood sampling of children with NSCLP is often performed during surgery.

We are continuing to test possibly associated (or “candidate”) chromosomal regions that have been identified in genome-wide scans and candidate genes that function in normal development of the face or have been identified in studies of mice. Evidence has been found of association for eight chromosomal regions. Four of which, 2q37, 11p12-14, 12q13 and 16p13, have also been identified in a second genomic scan of multiplex families from China. One region, defined by D11S1392, gave evidence suggesting the presence of an NSCLP locus in all three studies. These results suggest chromosomal regions that are being targeted in order to identify NSCLP loci. Studies are being completed on candidate genes and evidence has been found for association with a few of these genes. Additional studies are underway to confirm these findings.

Identification of genetic loci causing NSCLP will have multiple benefits. First, it will assist in diagnosis, counseling and treatments. Second, knowledge of high-risk genotypes may lead to the development of prevention programs in selected populations. Finally, it will lead to a better understanding of how the face develops.