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Yonghong Jiao, Dan Wang, Hongyan Jia, Qinglin Chang, Yi Liang, Qian Ma; Genotype-phenotype correlations in a Chinese cohort of CFEOM patients with KIF21A and TUBB3 mutations. Invest. Ophthalmol. Vis. Sci. 2021;62(8):2608.
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KIF21A and TUBB3 are two common pathogenic genes identified by congenital fibrosis of extraocular muscles (CFEOM) which is an inherited nonprogressive neuromyopathy. This study aims to explore the phenotype-genotype correlations in Chinese CFEOM patients with KIF21A and TUBB3 mutations, and to discover further understanding of gene functional.
Thirty-nine subjects from familial or sporadic CFEOM cases with clinical examinations, MRI findings and positive genetic test results were enrolled for retrospective case series study. MRI was used to evaluate orbital, encephalic, and intracranial nerve integrity. Ocular motor nerves diameters and extraocular muscle (EOM) volumes were measured.
Genetic testing indicated that 53.8% patients harbored KIF21A mutations (p.R954W, p.R954Q, p.F355S), 30.8% with TUBB3 mutations (p.R262C, p.R262H, p.R380C, p.E410K, p.S78T), and 15.4% with others. All familial patients were detected with pathogenic mutations in KIF21A (68.4%) or TUBB3 (31.6%). Among subjects with KIF21A and TUBB3 mutations, all subjects showed typical ocular manifestation; two subjects (9.5%) with KIF21A mutations and 4 subjects (33.3%) with TUBB3 mutations showed other systemic malformations (e.g., congenital finger contractures, funnel chest etc.). MRI revealed hypoplasia of oculomotor nerve (CN3) and the atrophy of corresponding extraocular muscles. Mean±SD CN3 diameter in TUBB3 group was 1.03±0.45 mm, slightly but not significantly smaller than the diameter in KIF21A group, which measured 1.11±0.39 mm. Fifteen subjects (71.4%) with KIF21A mutations had unilateral or bilateral abducens nerve (CN6) absence and one subject (6.3%) with TUBB3 mutations had bilateral absence. Meanwhile, SR, IR and LR volumes in subjects with KIF21A were significantly smaller than those in TUBB3 group (p＜0.001). Besides, the phenotypes of TUBB3 mutations were notably differ from each other. Five patients (66.7%) in TUBB3 had intellectual disabilities with dysplasia of the midline commissural structures (anterior commissure, corpus callosum etc.).
KIF21A and TUBB3 are hotspot mutation genes and KIF21A is the main pathogenic gene in Chinese CFEOM. CN3 and its innervated extraocular muscles are most often affected. TUBB3 group had more systemic malformations and brain developmental defects. Moreover, TUBB3 group had a better correspondence between genotype and phenotype.
This is a 2021 ARVO Annual Meeting abstract.
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