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.


METHODS
Interventional family study.


METHODS
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.


METHODS
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.


BACKGROUND
The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Khan
Arif O
AO
Division of Pediatric Ophthalmology, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia; Department of Genetics, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. arif.khan@mssm.edu
Khalil
Dania S
DS
Al Sharif
Latifa J
LJ
Al-Ghadhfan
Faisal E
FE
Al Tassan
Nada A
NA
D000328:Adult; D001483:Base Sequence; D002648:Child; D005260:Female; D005355:Fibrosis / Q000151:congenital; D018095:Germ-Line Mutation / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D016547:Kinesins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009030:Mosaicism; D009801:Oculomotor Muscles / Q000473:pathology*; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D013285:Strabismus / Q000175:diagnosis / Q000235:genetics*; D055815:Young Adult
D018398:Homeodomain Proteins; C119023:KIF21A protein, human; C491061:PHOX2A protein, human; D016547:Kinesins