Microcephaly-related global developmental delay caused by a pathogenic METTL5 splicing mutation in a Chinese family.

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.