FREM1 – BNAR Syndrome

FREM1 encodes an extracellular matrix protein critical for craniofacial, renal, and anorectal development. Bifid nose with or without anorectal and renal anomalies (BNAR) syndrome (MONDO:0012165) is characterized by nasal tip bifidity, anorectal malformations, and renal anomalies. The disorder follows an autosomal recessive inheritance pattern with biallelic loss-of-function or missense variants in FREM1.

Autosomal recessive inheritance is supported by ten affected individuals from four unrelated families harboring homozygous or compound heterozygous FREM1 variants (10 probands ([PMID:32926405]; [PMID:40605465])). All parents are unaffected carriers, consistent with full penetrance in the recessive state. No additional segregation beyond index cases has been reported.

The variant spectrum in BNAR includes missense, nonsense, and canonical splice site lesions. Notably, c.5622G>A (p.Trp1874Ter) has been observed as part of a compound heterozygous genotype in a fetal bilateral renal agenesis case ([PMID:40605465]). These variants disrupt FREM1 protein stability or transcript processing, leading to loss of function.

Functional studies in a Frem1-deficient mouse model demonstrate phenotypic concordance with human BNAR features. An ENU-induced homozygous missense allele, c.1687A>T (p.Ile563Phe), causes microphthalmia, renal agenesis, and rectal prolapse in mice, and fails to complement a p.Lys826Ter allele, confirming a loss-of-function mechanism ([PMID:23536828]). Additional genetic interaction assays reveal modulation of lung and kidney phenotypes by Gata4 and Slit3.

Conflicting reports of heterozygous FREM1 deletions associated with trigonocephaly have been refuted: a cohort of 20 developmental delay patients with heterozygous deletions showed no metopic suture closure defects, underscoring the recessive nature of BNAR ([PMID:33038106]). No studies have refuted the biallelic association.

Integration of clinical, genetic, and experimental data supports a Moderate clinical validity classification for FREM1 in BNAR syndrome. Biallelic loss-of-function variants segregate with disease and mouse models faithfully recapitulate key features. Key take-home: Genetic testing for FREM1 variants enables definitive diagnosis and informs clinical management in BNAR syndrome.

References

• Clinical genetics • 2020 • Bifid nose as the sole manifestation of BNAR syndrome, a FREM1-related condition. PMID:32926405
• Clinical genetics • 2025 • Non-Canonical Splice Site Variant in FREM1 Result in Fetal Renal Agenesis. PMID:40605465
• PloS one • 2013 • Novel frem1-related mouse phenotypes and evidence of genetic interactions with gata4 and slit3. PMID:23536828
• Clinical dysmorphology • 2021 • Heterozygous intragenic deletions of FREM1 are not associated with trigonocephaly. PMID:33038106

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