ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000009.11) (NC_000009.12)
  • Haploinsufficiency score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Haploinsufficiency phenotype comments:

FREM1 loss of function mutations are associated with autosomal recessive Manitoba-oculo-tricho-anal (MOTA) syndrome and bifid nose with or without anorectal and renal anomalies. Nathanson J et al 2013 PMID: 23401257 described compound heterozygous or homozygous loss of function mutations in affected patients. Five parents shown to be carriers for these mutations did not have an abnormal phenotype. Slavotinek AM et al 2011 PMID: 21507892 similarly showed 3 carrier parents with heterozygous deletions of exons 8 - 23, who were phenotypically normal. Vissers LE et al. 2011 PMID: 21931569 describe four patients with developmental delay and multiple congenital anomalies including trigonocephaly, who have large deletions in chromosome 9p which disrupt or completely delete FREM1. It is not possible to conclude that loss of one copy of FREM1 alone is sufficient to cause the trigonocephaly observed in these patients since the copy number changes are all large (> 2 Mb in size) and involve many other genes in addition to FREM1. This study also reported heterozygous missense mutations in unrelated patients with autosomal dominant trigonocephaly, however they do not provide evidence for haploinsufficiency of FREM1.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

No focal duplications of this gene have been reported to be associated with an abnormal phenotype at the time of this review.