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Xue Chen, Gang Liu, Kanxing Zhao, Qinghuai Liu, Chen Zhao; Maternal Germline Mosaicism of KIF21A Mutation Causes Complex Phenotypes in a Chinese Family with Congenital Fibrosis of Extraocular Muscles. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4551.
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To determine the causative mutation with its possible origin in a Chinese family with congenital fibrosis of extraocular muscles type 1 (CFEOM1), and to characterize the ocular phenotypes and lesions in the corresponding intracranial nerves.
Three affected siblings and their asymptomatic parents underwent comprehensive ophthalmic examinations and neuropathologic analysis by magnetic resonance imaging (MRI). KIF21A, PHOX2A and TUBB3genes were sequenced on the leukocyte-derived DNA to detect variants. Disease-linked haplotype was analyzed using 4 microsatellite markers across the KIF21A locus.
All 3 affected individuals displayed typical CFEOM1. MRI revealed complicated but consistent neural-muscular abnormalities in the 2 patients examined, including hypoplastic oculomotor nerves, completely absent of bilateral superior rectus (SR) muscles, and unusual unilateral absent of abducens nerve with remarkable atrophy of the corresponding lateral rectus (LR) muscle. A heterozygous hotspot mutation KIF21A c.2860C>T was identified in all patients, but absent in both parents. Haplotype analysis on the disease locus showed a likely maternal inheritance of the disease-associated haplotype to all 3 affected offsprings, strongly suggesting a maternal germline mosaicism of the mutation.
Germline mosaicism of KIF21A c.2860C>T is likely to cause the high occurrence of this mutation in population, and thus provides new insight into genetic counseling. KIF21A mutations could affect abducens nerve and cause complete absence of bilateral SR muscles. MRI characterization of new CFEOM1 phenotypes would assist clinical management.
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