Moxin Chen1,2, Rui Huang1,2, Yingjie Zhang1,2, Deyi Jasmine Zhu3, Qin Shu1,2, Pengcheng Xun4, Jing Zhang5,6, Ping Gu7,8, Lin Li9,10. 1. Department of Ophthalmology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 639 Zhizaoju Road, Huangpu District, 200011, Shanghai, China. 2. Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China. 3. Brooks School, North Andover, MA, USA. 4. Department of Global Value Access and Outcomes, Atara Biotherapeutics, Thousand Oaks, CA, USA. 5. Department of Ophthalmology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 639 Zhizaoju Road, Huangpu District, 200011, Shanghai, China. zhjingty@126.com. 6. Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China. zhjingty@126.com. 7. Department of Ophthalmology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 639 Zhizaoju Road, Huangpu District, 200011, Shanghai, China. guping2009@126.com. 8. Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China. guping2009@126.com. 9. Department of Ophthalmology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 639 Zhizaoju Road, Huangpu District, 200011, Shanghai, China. jannetlee1300@163.com. 10. Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China. jannetlee1300@163.com.
Abstract
PURPOSE: Congenital fibrosis of extraocular muscles type 1 (CFEOM1), a classical subtype of CFEOM, is characterized by restrictive ophthalmoplegia and ptosis. It is mainly caused by aberrant neural innervation of the extraocular muscles. This study aimed to investigate the genetic characteristics and clinical manifestations of CFEOM1 in Chinese families. METHODS: The clinical data, including ocular examinations, magnetic resonance imaging (MRI), and surgical procedures of affected individuals from 16 Chinese CFEOM1 families, were collected. The genomic DNA of 16 probands and their family members were sequenced for causative KIF21A gene mutations. Linkage analysis using microsatellite markers across KIF21A was also conducted. RESULTS: Affected individuals were presented with bilateral non-progressive ptosis, restricted horizontal eye movement, fixed infraduction of both eyes, compensatory chin-up head position, and neuromuscular abnormalities. Three heterozygous KIF21A mutations, c.2860C > T (p.R954W) (in eight families), c.2861G > T (p.R954L) (in two families), and c.2861G > A (p.R954Q) (in two families) were identified, which implied that hotspot mutations were common in Chinese CFEOM1 families. Germline Mosaicism was likely to be the cause of affected individuals with asymptomatic parents without KIF21A mutations presented in the eight families. Two affected individuals underwent modified levator muscle complex suspension surgery and achieved a good result without any complications. CONCLUSION: Instead of evaluating the whole CFEOM1 gene variant, hotspot mutations could be given priority for screening. The occurrence of germline mosaicism has to be taken into account in genetic counseling. Patients with CFEOM1 who have ptosis may benefit from an innovative surgical procedure called modified levator muscle complex suspension.
PURPOSE: Congenital fibrosis of extraocular muscles type 1 (CFEOM1), a classical subtype of CFEOM, is characterized by restrictive ophthalmoplegia and ptosis. It is mainly caused by aberrant neural innervation of the extraocular muscles. This study aimed to investigate the genetic characteristics and clinical manifestations of CFEOM1 in Chinese families. METHODS: The clinical data, including ocular examinations, magnetic resonance imaging (MRI), and surgical procedures of affected individuals from 16 Chinese CFEOM1 families, were collected. The genomic DNA of 16 probands and their family members were sequenced for causative KIF21A gene mutations. Linkage analysis using microsatellite markers across KIF21A was also conducted. RESULTS: Affected individuals were presented with bilateral non-progressive ptosis, restricted horizontal eye movement, fixed infraduction of both eyes, compensatory chin-up head position, and neuromuscular abnormalities. Three heterozygous KIF21A mutations, c.2860C > T (p.R954W) (in eight families), c.2861G > T (p.R954L) (in two families), and c.2861G > A (p.R954Q) (in two families) were identified, which implied that hotspot mutations were common in Chinese CFEOM1 families. Germline Mosaicism was likely to be the cause of affected individuals with asymptomatic parents without KIF21A mutations presented in the eight families. Two affected individuals underwent modified levator muscle complex suspension surgery and achieved a good result without any complications. CONCLUSION: Instead of evaluating the whole CFEOM1 gene variant, hotspot mutations could be given priority for screening. The occurrence of germline mosaicism has to be taken into account in genetic counseling. Patients with CFEOM1 who have ptosis may benefit from an innovative surgical procedure called modified levator muscle complex suspension.
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