Application of genetic analyses in studies of syndromic and non-syndromic cleft lip and palate

Abstract: Linkage analysis is one of the first and essential steps in the localization of human disease genes. In this study, the method was first applied in mapping of the disease in two families with isolated hyperparathyroidism (FIHP) to the hyperparathyroidism-jaw tumor (HPT-JT) syndrome locus at 1q21-q32. The results suggest that a sunset of FlHP families are a variant of HPT-JT. Loss of heterozygosity at 1q21-q32 was found in tumors from a FIHP and a HPT-JT family, implying that the gene involved is a tumor suppressor gene (Paper I). Genetic analyses were applied to the studies of syndromic and non-syndromic cleft lip and palate. Van der Woude syndrome (VWS), the most common form of syndromic cleft, has been mapped to 1q32-q41. Two Swedish and three Finnish families were mapped to 1q32-q41 and the critical region was tentatively refined to 130-kb by observing recombination and shared haplotypes in the families. Microdeletion of the VWS region was unlikely. Two Finnish families were unlinked to the VWS region in 1q thus providing the first evidence of genetic heterogeneity in VWS. All families were tested for the possible modifying effect on the cleft palate phenotype from a locus in 17p11.2-p11.1. Linkage was clearly excluded, meaning that the 17p locus is not a major modifying gene (Papers II, III). A Swedish boy and his mother who both have cleft lip and palate were examined for additional clinical featured. The presence of lip pits and a distinct toe malformation led to the diagnosis of popliteal pterygium syndrome (PPS). Our analysis showed that microdeletion of the 1q VWS region was unlikely but linkage to the region could not be excluded (Paper IV). Non-syndromic cleft lip with or without cleft palate (CLP) has been tentatively mapped to candidate loci in chromosome 4, chromosomes 2, 6 and 19 with heterogeneity. Linkage to these regions as well as the 1q VWS locus was tested in 19 Swedish multi-generation CLP families. Our results showed that the group of families was unlinked to any of these regions and heterogeneity was not evidenced. This might imply a new locus or loci in the Swedish CLP families, although linkage to individual loci could be hidden by insignificant heterogeneity in the family group. Results from the non-parametric linkage analysis were insignificant. Although linkage could not be confirmed with the limited sizes of these families, data from individual families will form the basis for future studies of candidate genes derived from these loci (Paper V). In summary, genetic linkage analyses have been applied to elucidate the genetic basis of syndromic and non-syndromic cleft lip and palate, generating important clinical and genetic data. These results will be incorporated into the ongoing gene mapping efforts of these diseases. Identification of the genes involved in cleft lip and palate is essential for the diagnosis, prediction and in the future treatment of these congenital malformations.