Congenital fibrosis of the extraocular muscles type 3 (CFEOM3) is rarely caused by mutations in KIF21A

Abstract

Abstract: : Purpose: Congenital fibrosis of the extraocular muscles (CFEOM) refers to several complex paralytic strabismus syndromes characterized by congenital restrictive ophthalmoplegia, often with accompanying ptosis. We have identified three CFEOM phenotypes (CFEOM1–3) and demonstrated that CFEOM1 results from mutations in the KIF21A gene and CFEOM2 from mutations in the PHOX2A gene. This study was conducted to elucidate if KIF21A and/or PHOX2A play any role in the pathogenesis of CFEOM3 and to delineate any genotype–phenotype correlation. Methods: We identified all pedigrees and sporadic individuals with CFEOM3 in our database, determined if the pedigrees were linked or consistent with linkage to the FEOM1, FEOM2, and/or FEOM3 loci, and screened the appropriate pedigrees and the sporadic individuals for mutations in KIF21A and PHOX2A using DHPLC and/or direct DNA sequencing. Results: We identified 12 CFEOM3 pedigrees and 10 CFEOM3 sporadic individuals in our database. Two CFEOM3 pedigrees were excluded because they independently mapped to the FEOM3. The structures of 6 of the 10 pedigrees permitted the generation of meaningful linkage data and, of these, three were linked or consistent with linkage to FEOM1, one to FEOM2, and four to FEOM3. KIF21A was screened in 17 probands and mutations were identified in 2 CFEOM3 pedigrees. One pedigree harbored a novel KIF21A mutation and one harbored the most common of the previously reported CFEOM1 mutations. None of CFEOM3 pedigrees or sporadic individuals harbored mutations in PHOX2A. Conclusions: KIF21A mutations are a rare cause of CFEOM3 and, therefore, KIF21A is the first gene associated with CFEOM3. In contrast, PHOX2A mutations are not likely to be associated with CFEOM3. Our results imply that variable CFEOM phenotypes with variable penetrance can be caused by KIF21A mutations and suggest a probable genotype–phenotype correlation.

Keywords: mutations • strabismus: etiology • ocular motor control