Molecular study of 33 families with Fraser syndrome new data and mutation review

Abstract

Fraser syndrome (FS) is an autosomal recessive malformation disorder characterized by cryptophthalmos, syndactyly, and abnormalities of the respiratory and urogenital tract. FS is considered to be the human equivalent of the murine blebbing mutants: in the mouse mutations at five loci cause a phenotype that is comparable to FS in humans, and thus far mutations in two syntenic human genes, FRAS1 and FREM2, have been identified to cause FS. Here we present the molecular analysis of 48 FS patients from 18 consanguineous and 15 nonconsanguineous families. Linkage analysis in consanguineous families indicated possible linkage to FRAS1 and FREM2 in 60% of the cases. Mutation analysis identified 11 new mutations in FRAS1 and one FREM2 mutation. Manifestations of these patients and previously reported cases with an FRAS1 mutation were compared to cases without detectable FRAS1 mutations to study genotype-phenotype correlations. Although our data suggest that patients with an FRAS1 mutation have more frequently skull ossification defects and low insertion of the umbilical cord, these differences are not statistically significant. Mutations were identified in only 43% of the cases suggesting that other genes syntenic to murine genes causing blebbing may be responsible for FS as well.

Next-generation sequencing identifies rare variants associated with Noonan syndrome

“…Two patients (NS100 and NS110) harbored novel variants in FRAS1 (Table S3 and Fig. S4), a causative gene for Fraser syndrome (MIM 219000), an autosomal recessive disorder characterized by cryptophthalmos and other malformations (43). Fraser syndrome is quite rare (incidence ∼1 in 250,000 live births and 1 in 10,000 still births), and therefore the carrier frequency is expected to be 1/100∼1/500.…”

“…S4). The latter domain is the most frequently mutated region of FRAS1 in Fraser syndrome (43). Although NS100 and NS110 are potential carriers for a disease-causing FRAS1 allele, the role, if any, of these mutations in the NS phenotype of these patients is unclear.…”

fras1shapes endodermal pouch 1 and stabilizes zebrafish pharyngeal skeletal development

“…Human FRAS1 lesions cause Fraser syndrome (McGregor et al, 2003;Slavotinek et al, 2006;van Haelst et al, 2008), a complex disorder with numerous variably expressed symptoms, including ear defects and other craniofacial birth defects (Fraser, 1962;Gattuso et al, 1987;Slavotinek and Tifft, 2002;Thomas et al, 1986;van Haelst et al, 2007). The symptoms of Fraser syndrome vary extensively in both presence and severity from one patient to another.…”

“…Subsequent studies revealed that other members of the FRAS1 protein complex (the Fraser complex) can cause Fraser syndrome (Jadeja et al, 2005;Shafeghati et al, 2008) or related diseases (Alazami et al, 2009;Slavotinek et al, 2011), explaining some of the causes of the different Fraser spectrum diseases. However, a wide range of symptoms are present even in patients carrying genetic lesions that are likely to severely disrupt FRAS1 function (van Haelst et al, 2008). For instance, siblings can show life and death differences in symptomatic expressivity (Prasun et al, 2007).…”

Mutations in GREB1L Cause Bilateral Kidney Agenesis in Humans and Mice

“…A large range of genetic heterogeneity has been highlighted by the identification of mutations, mostly at the heterozygous state, in more than 50 genes, many of them encoding transcription factors with a crucial role during nephrogenesis (e.g., HNF1B : 191830), and RET (MIM: 164761) in some case subjects with isolated BKA, or in KIF14 (MIM: 616258), FRAS1 (MIM: 219000), and FREM1 (MIM: 608980) in syndromic forms. 5,[8][9][10][11][12] However, in most BKA-affected fetuses, even when a monogenic cause is likely according to the genealogy, the mutated gene is unknown. In order to identify additional genes mutated in CAKUT, 30 case subjects from 15 families were analyzed by wholeexome sequencing (WES).…”