FREM1

Chr 9ARAD

FRAS1 related extracellular matrix 1

Also known as: BNAR, C9orf143, C9orf145, C9orf154, MOTA, TRIGNO2

NCBI Gene: 158326 ENSG00000164946 UniProt: Q5H8C1 OMIM: 608944

FREM1 encodes an extracellular matrix protein required for epidermal adhesion during embryonic development and plays a role in epidermal differentiation. Mutations cause bifid nose with or without anorectal and renal anomalies, Manitoba oculotrichoanal syndrome, and trigonocephaly 2, with both autosomal recessive and autosomal dominant inheritance patterns reported. These conditions primarily affect craniofacial development, with variable involvement of renal and anorectal systems.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The products of this gene play important roles both in embryonic development and as a modulator of the innate immune responses and inflammation. This gene encodes an extracellular matrix protein that is restricted to the dermis. It is secreted and forms complexes with FREM2 and FRAS1 gene products and is required to maintain epidermal adhesion during embryonic development. Pathogenic mutations in this gene have been implicated in Manitoba oculotrichoanal (MOTA) syndrome, bifid nose with or without anorectal and renal anomalies (BNAR syndrome), and congenital diaphragmatic hernia (CDH). A 715 aa isoform of this gene known as TILRR (Toll-like interleukin-receptor regulator) is expressed from an alternate promoter and is involved in controlling the inflammatory process. The encoded protein is a cell surface proteoglycan that is a co-receptor for IL-1 receptor type I (IL1RI). TILRR increases IL1R1 expression levels and regulates receptor function, leading to amplified activation of NF-kappaB and inflammatory responses. [provided by RefSeq, Apr 2026]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Bifid nose with or without anorectal and renal anomaliesMIM #608980

Manitoba oculotrichoanal syndromeMIM #248450

Trigonocephaly 2MIM #614485

UniProtBifid nose, with or without anorectal and renal anomalies

Clinical highlights

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.12

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — FREM1