Germline Mosaicism for KIF21A Mutation (p.R954L) Mimicking Recessive Inheritance for Congenital Fibrosis of the Extraocular Muscles.

Objective: To document the genotype for familial congenital fibrosis of the extraocular muscles (CFEOM) with apparent autosomal recessive inheritance.

Design: Interventional family study.

Participants: Two affected siblings, 3 asymptomatic siblings, and their 2 asymptomatic parents.

Methods: Ophthalmologic examination and candidate gene analysis (KIF21A and PHOX2A from venous blood samples) of the 2 affected siblings and their parents; confirmatory testing for 3 available asymptomatic siblings.

Main Outcome Measures: Significant clinical observations and results of gene testing.

Results: The 2 affected siblings had large-angle exotropia, moderate bilateral hypotropia, moderate bilateral ptosis, sluggish pupils, and almost complete ophthalmoloplegia with some abnormal synkinesis. The asymptomatic parents were not related and had unremarkable ophthalmic examinations. Four other siblings were normal by history; 3 underwent venous blood sampling for confirmatory testing. Candidate gene testing of PHOX2A, the gene for recessive CFEOM (CFEOM2), did not reveal mutation in the 2 patients or their parents. Sequencing of KIF21A, the gene for dominant CFEOM (CFEOM1), revealed heterozygous p.R954L in both affected individuals but in not in their parents or 3 asymptomatic siblings, consistent with parental germline mosaicism. Haplotype analysis suggested paternal inheritance but was not conclusive.

Conclusions: Parental germline mosaicism can mimic recessive inheritance in CFEOM and likely is underrecognized. Ophthalmologists should be aware of this phenomenon when counseling parents of children with apparent recessive (or de novo) hereditary eye disease. Unlike other reported KIF21A mutations that cause CFEOM1, the p.R954L variant seems to be associated with abnormal pupils.

Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.