Submission Details

KIF21A was first reported in relation to autosomal dominant congenital fibrosis of the extraocular muscles (CFEOM) in 2003 (Yamada et al., PMID:14595441). CFEOM is a syndrome of congenital nonprogressive bilateral ophthalmoplegia affecting the extraocular muscles innervated by the oculomotor and/or trochlear nerves. Classic presentations of CFEOM are characterized by ptosis, severe limitation of vertical gaze, and inability to raise either eye above the midline with variable limitation of the horizontal gaze. This disorder has historically been referred to as both CFEOM1 and CFEOM3, the latter characterized by a milder, sometimes unilateral presentation.Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity, CFEOM1 (OMIM:135700) and CFEOM3 (OMIM:135700). Evidence supporting this gene-disease relationship includes case-level, segregation, and experimental data. Eleven missense variants reported across 33 probands in seven publications (PMIDs: 14595441,15621877, 15621876, 18332320, 15223798, 19551685, 17511870) are included in this curation. Of the variants reported in this curation, all were absent from gnomAD and the most frequent variant (R954W) was reported in 21 probands, 9 of which were de novo observations. This specific variant is the most common for this syndrome, and variants at this residue (R954) account for the majority of cases. This residue has been shown to contain a CpG dinucleotide that is methylated, providing some insight into the high mutability of this region in KIF21A (PMID:15621877). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be gain of function. This gene-disease relationship is also supported by animal models and expression studies (PMIDs:24656932, 22465342). Knock-in mice containing the R954W variant have been shown to exhibit CFEOM phenotypes with minimal differences, and KIF21A has been shown to be expressed normally in human and murine extraocular and skeletal muscle cells. In summary, KIF21A is definitively associated with autosomal dominant CFEOM. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Brain Malformations Expert Panel on the meeting date 09/28/21 (SOP Version 8).