FREM1 – Oculotrichoanal Syndrome

FREM1 encodes an extracellular matrix protein critical for craniofacial, ocular, anorectal and renal development. Oculotrichoanal (MOTA) syndrome (MONDO:0009560) is an autosomal recessive disorder characterized by cryptophthalmos, trichiasis, hypertelorism and low anorectal malformations. Inheritance is autosomal recessive with pathogenic variants on both alleles of FREM1.

Initially, eight unrelated patients with MOTA syndrome and biallelic FREM1 mutations were described. A new 3.5-month-old male patient presented with bilateral incomplete cryptophthalmos, hypertelorism (HP:0000316), dysplastic ears (HP:0000377) and a correctable low anorectal malformation. Molecular analysis identified compound heterozygosity for c.3971T>G (p.Leu1324Arg) and c.4629delC (p.Phe1544SerfsTer?) in FREM1 (PMID:23112756). Total probands now number nine.

Phenotypic expansion includes prenatal bilateral renal agenesis in a fetus with compound heterozygous variants c.5622G>A (p.Trp1874Ter) and c.3274+4A>G causing aberrant splicing, underscoring renal involvement in the FREM1 spectrum (PMID:40605465).

Functional evidence from Frem1-deficient mice demonstrates microphthalmia, cryptophthalmos, renal agenesis, diaphragmatic hernia and rectal prolapse, faithfully recapitulating human MOTA features. A missense allele (c.1687A>T, p.Ile563Phe) in mice reduces protein stability and fails to complement the null allele; genetic interaction studies reveal modulation of lung and kidney phenotypes by Gata4 and Slit3 (PMID:23536828).

Conflicting evidence arises from homozygosity mapping in four Cree ancestry probands without coding FREM1 variants, suggesting potential non-coding regulatory mutations or locus heterogeneity (PMID:22690109).

Integration of clinical, genetic and animal model data supports a Strong gene–disease association. Additional cases and regulatory variant screening may further refine pathogenic mechanisms. Key take-home: Biallelic FREM1 variants are a clinically actionable cause of MOTA syndrome with consistent functional validation in vivo.

References

• Molecular syndromology • 2012 • MOTA Syndrome: Molecular Genetic Confirmation of the Diagnosis in a Newborn with Previously Unreported Clinical Features. PMID:23112756
• PloS one • 2013 • Novel frem1-related mouse phenotypes and evidence of genetic interactions with gata4 and slit3. PMID:23536828
• Molecular vision • 2012 • Evidence for additional FREM1 heterogeneity in Manitoba oculotrichoanal syndrome. PMID:22690109
• Clinical genetics • 2025 • Non-Canonical Splice Site Variant in FREM1 Result in Fetal Renal Agenesis. PMID:40605465

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