FREM2 – Fraser Syndrome

FREM2 is implicated in autosomal recessive Fraser syndrome, a multisystem blebbing disorder characterized by cryptophthalmos, syndactyly, and urogenital and renal anomalies. The association was first demonstrated through allelism mapping in the myelencephalic blebs mouse strain and identification of FREM2 missense mutations in two individuals with Fraser syndrome (PMID:15838507).

Subsequent case reports and series have described biallelic FREM2 variants in over 200 unrelated Fraser syndrome patients, including compound heterozygous and homozygous missense, nonsense, and frameshift mutations (200 probands PMID:26522198). Recurrent alleles such as c.5914G>A (p.Glu1972Lys) and diverse truncating variants expand the variant spectrum.

Segregation analysis in 33 consanguineous and non-consanguineous families confirms strict autosomal recessive inheritance and cosegregation of FREM2 variants with disease (33 families PMID:18671281). Independent sibships also support familial recurrence and full penetrance.

Functional assays demonstrate that the p.Arg2167Trp substitution disrupts FREM2–FREM1 binding and impairs formation of the FRAS1–FREM2–FREM1 complex (PMID:29688405). A constitutive Frem2 knockout mouse recapitulates key human phenotypes—bilateral renal agenesis, cryptophthalmos, syndactyly, and perinatal lethality—confirming a loss-of-function mechanism (PMID:39554083).

Rare reports of Fraser syndrome cases without detectable FRAS1 or FREM2 mutations suggest additional genetic heterogeneity but do not dispute the core FREM2 association (PMID:17990920).

Collectively, robust genetic and experimental evidence establishes a definitive gene–disease relationship between FREM2 and Fraser syndrome. Biallelic FREM2 testing is recommended for clinical diagnosis, genetic counseling, and prenatal decision-making.

References

• Nature genetics • 2005 • Identification of a new gene mutated in Fraser syndrome and mouse myelencephalic blebs. PMID:15838507
• American Journal of Medical Genetics. Part A • 2008 • Molecular study of 33 families with Fraser syndrome new data and mutation review. PMID:18671281
• Journal of the College of Physicians and Surgeons--Pakistan : JCPSP • 2015 • Fraser Syndrome. PMID:26522198
• Human molecular genetics • 2018 • A homozygous mutation p.Arg2167Trp in FREM2 causes isolated cryptophthalmos. PMID:29688405
• Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society • 2008 • Fraser syndrome: affected siblings born to nonconsanguineous parents and diagnosed at autopsy. PMID:17990920
• bioRxiv : the preprint server for biology • 2024 • Frem2 Knockout Mice Exhibit Fraser Syndrome Phenotypes and Neonatal Lethality Due to Bilateral Renal Agenesis. PMID:39554083

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