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Background  Congenital fibrosis of the extraocular muscles types 1 and 3 (CFEOM1/CFEOM3) are autosomal dominant strabismus disorders that appear to result from maldevelopment of ocular nuclei and nerves. We previously reported that most individuals with CFEOM1 and rare individuals with CFEOM3 harbor heterozygous mutations in  KIF21A .  KIF21A  encodes a kinesin motor involved in anterograde axonal transport, and the familial and  de novo  mutations reported to date predictably alter one of only a few KIF21A amino acids – three within the third coiled-coil region of the stalk and one in the distal motor domain, suggesting they result in altered KIF21A function. To further define the spectrum of  KIF21A  mutations in CFEOM we have now identified all CFEOM probands newly enrolled in our study and determined if they harbor mutations in  KIF21A .    Results  Sixteen CFEOM1 and 29 CFEOM3 probands were studied. Three previously unreported  de novo  KIF21A mutations were identified in three CFEOM1 probands, all located in the same coiled-coil region of the stalk that contains all but one of the previously reported mutations. Eight additional CFEOM1 probands harbored three of the mutations previously reported in  KIF21A ; seven had one of the two most common mutations, while one harbored the mutation in the distal motor domain. No mutation was detected in 5 CFEOM1 or any CFEOM3 probands.    Conclusion  Analysis of sixteen CFEOM1 probands revealed three novel  KIF21A  mutations and confirmed three reported mutations, bringing the total number of reported  KIF21A  mutations in CFEOM1 to 11 mutations among 70 mutation positive probands. All three new mutations alter amino acids in heptad repeats within the third coiled-coil region of the KIF21A stalk, further highlighting the importance of alterations in this domain in the etiology of CFEOM1.

Three novel mutations in KIF21A highlight the importance of the third coiled-coil stalk domain in the etiology of CFEOM1