Li Qianqian, Zhu Xiaofan, Yu Chenguang, Shang Lin, Li Ranran, Wang Xia, Yang Yaping, Meng Jingjing, Kong Xiangdong
Genetics and Prenatal Diagnosis Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Front Genet. 2022 Feb 3;12:780363. doi: 10.3389/fgene.2021.780363. eCollection 2021.
External ophthalmoplegia with rib and vertebral anomalies (EORVA) is characterized by congenital nonprogressive external ophthalmoplegia, ptosis, scoliosis, torticollis, vertebral, and rib anomalies, caused by homozygous mutations in the myogenic factor 5 gene () located on chromosome 12q21.31. Uniparental disomy (UPD) is a rare inheritance of a pair of chromosomes originating from only one parent. This study describes a case of an 8-year-old boy with ptosis, scoliosis, and dysmorphic hypoplastic ribs with fusion anomalies. Trio-based exome sequencing (trio-ES) identified a novel homozygous mutation c.191delC (p.Ala64Valfs33) in in the proband, with the father being heterozygous and the mother wild-type, as verified by Sanger sequencing. UPD identified from trio-ES variant call format data suggested the possibility of paternal UPD of chromosome 12 (UPD12pat) in the proband, further confirmed to be a complete isodisomy type of UPD by genome-wide single nucleotide polymorphism array. MYF5 was significantly downregulated by 69.14% (* < 0.01) in HeLa cells transfected with mutant containing c.191delC compared to those transfected with the wild-type , resulting in a truncated protein with a size of ∼20 kDa. In conclusion, this study identified a novel homozygous mutation in , broadening the genetic spectrum of EORVA and further deepening the understanding of this rare disease.
伴有肋骨和脊椎异常的外眼肌麻痹（EORVA）的特征为先天性非进行性外眼肌麻痹、上睑下垂、脊柱侧凸、斜颈、脊椎和肋骨异常，由位于12q21.31染色体上的肌源性因子5基因（）的纯合突变引起。单亲二体（UPD）是一对仅来自一个亲本的染色体的罕见遗传方式。本研究描述了一名8岁男孩的病例，该男孩患有上睑下垂、脊柱侧凸以及伴有融合异常的发育不良畸形肋骨。基于三联体的外显子组测序（trio-ES）在先证者中鉴定出一个新的纯合突变c.191delC（p.Ala64Valfs*33），经桑格测序验证，父亲为杂合子，母亲为野生型。从trio-ES变异调用格式数据中鉴定出的UPD提示先证者存在12号染色体父源单亲二体（UPD12pat）的可能性，通过全基因组单核苷酸多态性阵列进一步确认为完全同二聚体型的UPD。与转染野生型的HeLa细胞相比，转染含有c.191delC的突变体的HeLa细胞中MYF5显著下调69.14%（**<0.01），导致产生一个大小约为20 kDa的截短蛋白。总之，本研究在中鉴定出一个新的纯合突变，拓宽了EORVA的遗传谱，进一步加深了对这种罕见疾病的理解。
