Submission Details

Variants in KIF11 were first associated with autosomal dominant inheritance of Microcephaly, lymphedema, chorioretinopathy syndrome, MCLMR, in 2012 (Ostergaard et al., 22284827). Over 16 probands reported unique heterozygous variants in this gene including five frameshift, three missense variants in highly conserved amino acid residues, two large deletions covering entire exons, two canonical splice site variants, as well as four stop gained. De novo variants were reported in six probands in two publications (Ostergaard et al., 22284827; Hull et al., 31077665). In addition, variants segregate in five additional family members in a large multi-generational pedigree (Ostergaard et al., 22284827). This gene-disease association is supported by expression studies which show expression in the retinal pigment epithelium, the inner segment, and the ciliary region of the photoreceptor layer, and the outer plexiform layers. Additional localization studies with markers specific for cilium and centrioles show expression in centrioles, basal bodies, and the connecting cilia of photoreceptor cells (Birtel et al., 28785766), however the role in retinal biology is still unknown. This gene has also been implicated in familial exudative vitreoretinopathy, FEVR, associated with microcephaly with overlapping clinical features (Hull et al., 31077665). More evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence (12.5 pts.) has been reached. In summary, KIF11 is definitively associated with autosomal dominant MCLRD, and this has been has been upheld over time.