Zhou Xiaoyan, Teng Congcong, Zhao Wenjing, Yang Wen, Yang Yuecheng, Chen Qing, He Ming, Zhang Jie
Department of Medical Genetics, The First People's Hospital of Yunnan Province/the Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650500, Yunnan, China.
Yunnan Provincial Key Laboratory for Birth Defects and Genetic Diseases, The First People's Hospital of Yunnan Province, Kunming, 650500, Yunnan, China.
J Hum Genet. 2025 Jun 11. doi: 10.1038/s10038-025-01354-w.
Microcephaly-related global developmental delay (GDD) and intellectual disability (ID) are characterized by a broad spectrum of neurodevelopmental impairments and encompass a multitude of causal factors. METTL5, a critical component involved in 18S rRNA methylation, has garnered considerable attention owing to its pivotal role in the pathogenesis of GDD and ID associated with microcephaly. A comprehensive physical examination and developmental assessment were performed for a 2-year-old girl presenting with symptoms of GDD and primary microcephaly. Whole-exome sequencing (WES) was performed to identify the pathogenic variant, and Sanger sequencing confirmed the mutation. To further investigate the pathogenicity of the mutation, minigene splicing assays, in vivo RT-PCR and bioinformatics analysis were employed. The WES identified a METTL5 homozygous intron mutation (NM_014168.4: c.224+5 G > A) in the proband. Sanger sequencing further validated the mutation in the family. Minigene assays and in vivo RT-PCR assays demonstrated exon 2 skipping, resulting in a 115-bp deletion in the mutated sequence. Bioinformatics analysis confirmed the pathogenicity of the mutation. For the first time, this study reported that a homozygous mutation (c.224+5 G > A) in the METTL5 gene led to microcephaly-related GDD in a Chinese family. Meantime, the report has validated the pathogenicity of intronic mutations and expanded the mutational spectrum of the METTL5 gene. Thus, this study aids our understanding of the role of METTL5 in GDD and provides a theoretical foundation for the prevention of this disease.
小头畸形相关的全面发育迟缓（GDD）和智力障碍（ID）的特征是广泛的神经发育障碍，且包含多种致病因素。METTL5是参与18S rRNA甲基化的关键成分，因其在与小头畸形相关的GDD和ID发病机制中的关键作用而备受关注。对一名出现GDD症状和原发性小头畸形的2岁女孩进行了全面的体格检查和发育评估。进行全外显子组测序（WES）以鉴定致病变异，Sanger测序证实了该突变。为进一步研究该突变的致病性，采用了小基因剪接分析、体内逆转录聚合酶链反应（RT-PCR）和生物信息学分析。WES在先证者中鉴定出一个METTL5纯合内含子突变（NM_014168.4: c.224+5 G > A）。Sanger测序进一步验证了该家族中的突变。小基因分析和体内RT-PCR分析显示外显子2跳跃，导致突变序列中出现115 bp的缺失。生物信息学分析证实了该突变的致病性。本研究首次报道METTL5基因中的纯合突变（c.224+5 G > A）导致一个中国家系出现小头畸形相关的GDD。同时，该报告验证了内含子突变的致病性，并扩大了METTL5基因的突变谱。因此，本研究有助于我们理解METTL5在GDD中的作用，并为该病的预防提供理论基础。
