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 phenotype comment: No focal duplications of this gene have been reported to be associated with an abnormal phenotype at the time of this review.
NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.