Molecular Genetics
In 5 families with Fraser syndrome, McGregor et al. (2003) identified 5 homozygous mutations in the FRAS1 gene (e.g., 607830.0001), which encodes a putative extracellular matrix (ECM) protein.
In 2 families with Fraser syndrome unlinked to the FRAS1 gene, Jadeja et al. (2005) found a homozygous missense mutation in the FREM2 gene (608945.0001).
In an infant girl with Fraser syndrome, Slavotinek et al. (2006) identified compound heterozygosity for a deletion (607830.0006) and an insertion (607830.0007) in the FRAS1 gene, inherited from her mother and her father, respectively.
Cavalcanti et al. (2007) described 2 stillborn Brazilian male sibs, born at 25 and 29 weeks' gestation, respectively. One sib appeared to have a lethal form of ablepharon-macrostomia syndrome (AMS; 200110) or an intermediate phenotype between AMS and Fraser syndrome, and the other had classic Fraser syndrome. Analysis of the FRAS1 gene revealed homozygosity for a splice site mutation (607830.0008), resulting in a severely truncated protein in both sibs and heterozygosity for the mutation in both parents. Cavalcanti et al. (2007) concluded that a phenotype resembling AMS is a rare clinical expression of Fraser syndrome, with no obvious genotype/phenotype correlation.
In a female fetus with a normal karyotype and cryptophthalmos, ambiguous external genitalia, syndactyly, bilobed lungs, bilateral renal agenesis, hypoplastic bladder, and agenesis of internal genitalia with streak ovaries, Shafeghati et al. (2008) identified homozygosity for a splice site mutation in the FREM2 gene (608945.0002). The consanguineous Iranian parents were heterozygous for the mutation. An earlier pregnancy had resulted in the intrauterine death at 30 weeks of gestation of a male fetus with a normal karyotype in whom the diagnosis of Fraser syndrome was suggested by the presence of cryptophthalmos, syndactyly, ambiguous genitalia, imperforate anus, bilateral renal agenesis, pulmonary hypoplasia, and hydrocephalus. The authors noted that the findings in the sibs were consistent with classic Fraser syndrome.
Among 18 consanguineous families with Fraser syndrome, van Haelst et al. (2008) found 9 families with linkage to FRAS1, 3 families to FREM2, and 3 families to both genes. Six families did not link to either locus, indicating genetic heterogeneity. Among a larger group of 33 families, including the 18 consanguineous families, molecular analysis identified 11 novel mutations in the FRAS1 gene in 10 families and 1 mutation in the FREM2 gene (608945.0003) in 1 family. A literature review of genotype/phenotype correlations suggested that patients with FRAS1 mutations have more frequent skull ossification defects and a low insertion of the umbilical cord compared to patients without a FRAS1 mutation, but the findings were not statistically significant.
Read more about this topic: Fraser Syndrome