Manitoba Oculotrichoanal Syndrome (MOTA) via the FREM1 Exon 8-23 Deletion

Manitoba oculotrichoanal syndrome (MOTA) is clinically characterized by eyelid colobomas, cryptophthalmos (hidden rudimentary eye), anophthalmia/microphthalmia, an aberrant hairline (unilateral or bilateral wedge-shaped extension of the anterior hairline from the temple region to the ipsilateral eye), a bifid or broad nasal tip, and gastrointestinal anomalies (omphalocele and anal stenosis) (Li et al. 2008; Slavotinek et al. 2011).

Manitoba oculotrichoanal syndrome (MOTA) is inherited in an autosomal recessive manner. Loss of function variants in FREM1 are reported to be causative for MOTA and Bifid Nose Renal Agenesis and Anorectal malformations (BNAR) syndrome, which are milder than Fraser syndrome (Nathanson et al. 2013; Slavotinek et al. 2011). The FREM1 encoded protein localizes underneath the lamina densa of epithelial basement membrane and is involved in the structural adhesion of skin epithelium to its underlying mesenchyme by forming a macromolecular ternary complex (Petrou et al. 2008). Dysfunction of any of this protein due to pathogenic variants in this gene results in the collapse of the protein assembly.

So far, ~20 pathogenic variants in FREM1 (nonsense, missense, splicing, small and gross deletions and complex genomic rearrangements) have been reported (Human Gene Mutation Database).

The FREM1 exon 8–23 deletion (60.1-kb) (chr9:14,780,425-14,840,536) involving exons 8 through 23 specific to MOTA syndrome is seen in aboriginal patients of the Island Lake region of Northern Manitoba (Li et al. 2008; Slavotinek et al. 2011).

This specific deletion is seen in Aboriginal Manitoba oculotrichoanal syndrome patients of the Island Lake region of Northern Manitoba.

This test involves amplification of patient DNA with specific pairs of PCR primers that flank the FREM1 exon 8–23 deletion as well as primers within the deleted region to distinguish heterozygotes from homozygotes.