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Identification of KIF21A Mutations as a Rare Cause of Congenital Fibrosis of the Extraocular Muscles Type 3 (CFEOM3)

¹From the Departments of Genetics and ²²Neurology, Children’s Hospital, Boston, Massachusetts; the ²Harvard Medical School, Boston, Massachusetts; the ³Division of Neuro-ophthalmology, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia; the ⁴Department of Ophthalmology, Ankara Güven Hospital, Ankara, Turkey; the ⁵Department of Ophthalmology, University of Texas Health Science Center, San Antonio, Texas; the ⁶Department of Ophthalmology, Sligo General Hospital, County Sligo, Ireland; the ⁷Gene Mapping Lab, Pediatric Hematology Unit, Department of Pediatrics, Hacettepe University Medical Faculty, Ankara, Turkey; the ⁸Department of Ophthalmology, Geisinger Medical Institute, Danville, Pennsylvania; the ⁹Departments of Ophthalmology and Neurology and the Jules Stein Eye Institute, University of California Los Angeles, Los Angeles, California; the ¹⁰Royal Children’s Hospital, Department of Ophthalmology, University of Queensland, Brisbane, Australia; the ¹¹Department of Ophthalmology, University of Leicester, Leicester, United Kingdom; the ¹²University Eye Clinic, Bonn, Germany; the ¹³University of Melbourne, Department of Ophthalmology, Royal Victorian Eye and Ear Hospital, Melbourne, Australia; ¹⁴Instituto de Otorrinolaringología, San Bernardino, Caracas, Venezuela; the ¹⁵Children’s Hospital of Los Angeles, Doheny Eye Institute, University of Southern California, Los Angeles, California; the ¹⁶Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; ¹⁷Cole Eye Institute, the Cleveland Clinic Foundation, Cleveland, Ohio; ¹⁸Dipartimento di Scienze Oftalmologiche, Facoltà di Medicina e Chirurgia, Università degli Studi di Napoli "Federico II" Napoli, Italy; the ¹⁹JKA Institute of Strabismology and Dr. H. L. Patney Memorial Eye Clinic, Rajkot, India; the ²⁰Department of Ophthalmology, Hospital de Niños "Roberto del Rio," Santiago, Chile; and the ²¹Department of Ophthalmology, Harvard Medical School and the Massachusetts Eye and Ear Infirmary, Boston, Massachusetts.

PURPOSE. Three congenital fibrosis of the extraocular muscles phenotypes (CFEOM1–3) have been identified. Each represents a specific form of paralytic strabismus characterized by congenital restrictive ophthalmoplegia, often with accompanying ptosis. It has been demonstrated that CFEOM1 results from mutations in KIF21A and CFEOM2 from mutations in PHOX2A. This study was conducted to determine the incidence of KIF21A and PHOX2A mutations among individuals with the third CFEOM phenotype, CFEOM3.

METHODS. All pedigrees and sporadic individuals with CFEOM3 in the authors’ database were identified, whether the pedigrees were linked or consistent with linkage to the FEOM1, FEOM2, and/or FEOM3 loci was determined, and the appropriate pedigrees and the sporadic individuals were screened for mutations in KIF21A and PHOX2A.

RESULTS. Twelve CFEOM3 pedigrees and 10 CFEOM3 sporadic individuals were identified in the database. The structures of eight of the pedigrees permitted the generation of meaningful linkage data. KIF21A was screened in 17 probands, and mutations were identified in two CFEOM3 pedigrees. One pedigree harbored a novel mutation (2841GA, M947I) and one harbored the most common and recurrent of the CFEOM1 mutations identified previously (2860CT, R954W). None of CFEOM3 pedigrees or sporadic individuals harbored mutations in PHOX2A.

CONCLUSIONS. The results demonstrate that KIF21A mutations are a rare cause of CFEOM3 and that KIF21A mutations can be nonpenetrant. Although KIF21A is the first gene to be associated with CFEOM3, the results imply that mutations in the unidentified FEOM3 gene are the more common cause of this phenotype.

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