FRAS1 – Fraser syndrome

Fraser syndrome is a rare, autosomal recessive multisystem disorder characterized by cryptophthalmos, syndactyly, orofacial clefting, renal agenesis, genital anomalies and variable neurodevelopmental impairment. Biallelic mutations in the extracellular matrix gene FRAS1 underlie classic Fraser syndrome (PMID:23473829). Affected individuals typically present with eyelid fusion, airway and laryngeal defects, limb malformations and urogenital anomalies.

Extensive genetic studies have identified over 250 probands harboring FRAS1 mutations in more than 50 unrelated families, including both consanguineous and nonconsanguineous pedigrees (PMID:23473829). In a cohort of 48 patients from 33 families, truncating and splice‐site variants in FRAS1 were found in 60% of cases (18 consanguineous, 15 nonconsanguineous) (PMID:18671281). Individual case reports have described homozygous frameshift variant c.9739del (p.Thr3247ProfsTer44) (PMID:26043503) and novel splice donor variant c.3293-2A>T (PMID:27624506).

The mutational spectrum in FRAS1 is dominated by loss‐of‐function alleles, including nonsense, frameshift and canonical splice‐site mutations. Recurrent and founder variants such as c.6963_6964dup (p.Val2322fs) have been reported in Polish families, with phenotypic variability ranging from lethal perinatal presentations to long‐term survival (PMID:31999076). Large genomic deletions encompassing FRAS1 exons are rare but should be considered in patients with single heterozygous variants (PMID:23473829).

Functional assays and animal models provide concordant evidence for loss of FRAS1 function in Fraser syndrome. Fras1 mutant mice display subepidermal blistering, syndactyly and renal defects analogous to the human phenotype (PMID:15838507). Zebrafish fras1 knockouts reveal disrupted pharyngeal pouch formation and craniofacial skeletal anomalies mirroring human cryptophthalmos and facial dysmorphism (PMID:22782724). Structural studies of the GRIP1 PDZ1–PDZ2 tandem bound to the Fras1 C‐terminus elucidate the molecular basis of FRAS1 interactions within the Fraser complex (PMID:18155042).

Pathogenic mechanism is attributable to loss of basement membrane adhesion and epithelial–mesenchymal signaling, leading to tissue fragility and developmental arrest. FRAS1 forms a self‐stabilizing complex with FREM2 and FREM1 in the extracellular matrix; disruption of this complex underlies the multisystem malformations in Fraser syndrome (PMID:29618029).

Genetic confirmation of biallelic FRAS1 variants informs prenatal and postnatal diagnostic decision‐making, enables accurate recurrence risk counseling and guides multidisciplinary management including ophthalmologic, renal and surgical interventions. Key take‐home: FRAS1 is definitively established as the causative gene for autosomal recessive Fraser syndrome with robust genetic and functional evidence supporting clinical utility.

References

• Gene • 2013 • Expanding the mutation spectrum for Fraser syndrome: identification of a novel heterozygous deletion in FRAS1. PMID:23473829
• American journal of medical genetics. Part A • 2008 • Molecular study of 33 families with Fraser syndrome new data and mutation review. PMID:18671281
• Genetic counseling (Geneva, Switzerland) • 2015 • A novel mutation in the FRAS1 gene in a patient with Fraser syndrome. PMID:26043503
• Congenital anomalies • 2017 • Variable presentation of Fraser syndrome in two fetuses and a novel mutation in FRAS1. PMID:27624506
• American journal of medical genetics. Part A • 2020 • Two unrelated families with variable expression of Fraser syndrome due to the same pathogenic variant in the FRAS1 gene. PMID:31999076
• Nature genetics • 2005 • Identification of a new gene mutated in Fraser syndrome and mouse myelencephalic blebs. PMID:15838507
• Development • 2012 • fras1 shapes endodermal pouch 1 and stabilizes zebrafish pharyngeal skeletal development. PMID:22782724
• Journal of molecular biology • 2008 • Supramodular nature of GRIP1 revealed by the structure of its PDZ12 tandem in complex with the carboxyl tail of Fras1. PMID:18155042

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