van Haelst, MM; (2006) Clinical and molecular genetics of Fraser syndrome. Doctoral thesis , UCL (University College London).

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Abstract

Fraser syndrome (FS MIM 219000) is a rare, heterogeneous congenital malformation disorder characterized by cryptophthalmos, syndactyly and urogenital defects. The entity is named after George Fraser who described two unrelated patients with the same congenital malformation disorder consisting of cryptophthalmos, ear anomalies, genital anomalies and syndactyly. More than 250 cases have thus far been reported in the literature. Robin Winter had speculated that FS is the human equivalent of the murine blebbing mutants in which mutations at five loci give the same phenotype as FS. Mutations in two human genes are known to cause FS and there are three further candidate genes. FRAS1, the first locus identified, encodes an Extracellular Matrix (ECM) protein whose domain structure suggests a structural role within the ECM as well as in cell signalling. There are several genes similar to FRAS1 in the human genome. These are called FREM1-3 (Fras-Related-Extracellular-Matrixl-3). In patients with FS, missense mutations have recently been identified in a second gene, FREM2. The other FREM genes have not been associated with FS as yet. Mutations in Grip! have been identified in eye blebbing (eb) mutants. To date, no GRIP1 mutations have been identified in FS patients. Clinical data and DNA samples were collected from 59 affected individuals from 25 consanguineous and 15 non-consanguineous families. Evaluation of the clinical findings in this group revealed a higher frequency of abnormalities of the skull, larynx, umbilicus, urinary tract and anus, whereas mental retardation and cleft lip/ palate were less often observed than previously reported. Mutation analysis of the genes known or suspected to be involved in FS resulted in the identification of six FRAS1 mutations and two FREM2 mutations. Linkage analysis in consanguineous families indicated further evidence of linkage to FRAS1, FREM2, FREM1 and GRIP1. Genotype-phenotype analysis revealed that skull ossification defects, umbilical, urinary tract, and anorectal abnormalities were more frequently reported in patients with a FRAS1 mutation than in all other FS patients. Based on these results the existing diagnostic criteria were re evaluated and the definition of new diagnostic criteria for FS is suggested here along with a discussion of the findings.

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