Thorough evaluation of a novel splice variant in a female patient with MED12-related intellectual disability

Mediator complex subunit 12 (MED12) functions as a member of a multiprotein complex to regulate the fundamental process of transcription activation and repression. MED12-related disorders include X-linked syndromes and nonspecific intellectual disability, which display complex and gender-specific genotype-phenotype relationships. This study aimed to evaluate a novel splice variant in a female patient with MED12-related nonspecific intellectual disability. DNA sequencing identified the heterozygous intronic variant in the MED12 gene, NM_005120.3:c.397-12A > G. Bioinformatic analysis suggested a damaging effect, and subsequent transcriptome sequencing and individual transcript analysis confirmed aberrant splicing, including Exon 4 skipping and an 11 bp insertion from Intron 3. X-chromosome inactivation analysis revealed a moderately skewed pattern, consistent with reduced MED12 expression. More importantly, using in vitro minigene assays, we directly proved that this variant leads to the production of both abnormal transcripts and a remaining amount of normal ones, contributing to relatively mild disease symptoms in our patient. Collectively, our findings support the pathogenicity of this identified variant, which is classified as pathogenic per American College of Medical Genetics and Genomics guidelines, and diagnose the patient with MED12-related nonspecific intellectual disability. This study highlights the importance of integrating multiple molecular biology tools to diagnose and understand MED12-related disorders.