Rare syndromic craniosynostosis or isolated multisuture synostosis

Gene: FREM1

Comment on list classification: Although there are five cases with heterozygous variants in FREM1 gene associated with craniosynostosis/ trigonocephaly, there is also conflicting evidence suggesting there is no association of heterozygous variants in this gene with craniosynostosis. Hence, this gene can only be rated AMBER with the current evidence.

Created: 11 May 2023, 6:06 p.m. | Last Modified: 11 May 2023, 6:06 p.m.

Panel Version: 4.63

As reviewed by Rebecca Tooze (University of Oxford), PMID:33937142 reported the identification of FREM1 variants in two unrelated cases of craniosynostosis (one having multiple sutures and other with metopic craniosynostosis) and PMID:33288889 reported deletion of regions encompassing FREM1 gene in two cases from Norwegian cohort with craniosynostosis.

PMID:33038106 reported that homozygous FREM1 deletions are associated with Manitoba oculotrichoanal syndrome (MOTA, MIM #248450), while cases with heterozygous deletions had no associations with trigonocephaly in this cohort.

As reviewed by Tracy Lester (Genetics laboratory, Oxford UK), PMID:21931569 reported CNVs affecting FREM1 in five cases with trigonocephaly and heterozygous variants in FREM1 in three cases with trigonocephaly.

This gene has been associated with trigonocephaly in OMIM (MIM #614485), while it has been associated with Manitoba oculotrichoanal syndrome in both OMIM (MIM #248450) and Gene2Phenotype (with 'definitive' rating).

Created: 11 May 2023, 6:01 p.m. | Last Modified: 11 May 2023, 6:01 p.m.

Panel Version: 4.59

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Trigonocephaly 2, OMIM:614485

Publications

• 21931569
• 33038106
• 33288889
• 33937142

I don't know

• In a Norwegian cohort two 9p deletions were identified in patients with craniosynostosis, developmental delay, and reduced vision: g. 204193_ 18073357del (17.8Mb) and g.13638428_ 17121764del (3.5Mb) (Tønne et al., 2021).
• Two out of 28 patients with craniosynostosis in the Saudi Arabia cohort harboured FREM1 variants: (1) a heterozygous de novo variant in an individual with multi-suture synostosis: c.916_936dup; p.(Glu306_Leu312dup), (2) and two variants in cis in a family with metopic synostosis: c.4023C>G; p.(Cys1341Trp), and c.4564G>A; p.(Val1522Met) (Alghamdi et al., 2021).

Created: 2 Mar 2023, 1:27 p.m. | Last Modified: 2 Mar 2023, 1:27 p.m.

Panel Version: 3.4

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Red List (low evidence)

Vissers et al 2011 report CSS in 3/104 cases but the variants in these cases are also in controls (from Zollino et al). Evidence in original paper poor quality and no independent confirmation. Biallelic FREM1 mutations do cause FND (AW) ; Review on behalf of Tracy Lester and Andrew Wilkie

Created: 5 Mar 2019, 11:33 a.m.

Phenotypes
bifid nose; Manitoba oculotrichoanal syndrome; trigonocephaly

I don't know

This gene was part of an initial gene list collated by Tracy Lester, Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, February 2019 on behalf of the GMS Musculoskeletal Specialist Group; Gene symbol submitted: FREM1; Suggested initial gene rating: red

Created: 5 Mar 2019, 11:21 a.m.

Red List (low evidence)

One de novo mutation in Vissers paper but evidence for association considered weak overall; note FREM1 homozygous mutations associated with BNAR/MOTA syndromes in which craniosynostosis is not a feature

Created: 14 Sep 2015, 1:31 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
metopic synostosis

Publications

• 21931569