Germline Mosaicism for KIF21A Mutation (p.R954L) Mimicking Recessive Inheritance for Congenital Fibrosis of the Extraocular Muscles
Received 21 February 2009; received in revised form 9 May 2009; accepted 12 June 2009. published online 05 November 2009.
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.
Available online: November 5, 2009.
1Division of Pediatric Ophthalmology, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
2Department of Genetics, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
Correspondence: Arif O. Khan, MD, Division of Pediatric Ophthalmology, King Khaled Eye Specialist Hospital, P. O. Box 7191, Riyadh 11462, Saudi Arabia
Manuscript no. 2009-253.
Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
ABSTRACT