Background: Paired Box 2 (PAX2, NM_000278.5) encodes paired box gene 2, one of many human homologs of the Drosophila melanogaster gene prd. PAX2-related disorder is an autosomal dominant disorder associated with renal and eye abnormalities.

Methods: In this study, both monochorionic diamniotic twins presenting bilateral renal agenesis were subjected to investigation. The pregnancy was terminated and muscular tissue of the fetus was analyzed by trio whole exome sequencing (WES). The target sequence was verified by Sanger sequencing at the genome level. In vitro Minigene model was constructed and the transcribed cDNA was subjected to Sanger sequencing to explore the splicing effect of the suspected mutation.

Results: The synonymous mutation PAX2 c.792G>A was detected in both twins, but not in the parents or the family's firstborn. Although this mutation did not alter the amin acid sequence, minigene splice analysis confirmed that c.792G>A resulted in exon 6 skipping, leading to aberrant mRNA splicing.

Conclusions: PAX2 c.792G>A is the first pathogenic synonymous mutation ever documented. It has a significant impact on mRNA splicing and leads to developmental abnormalities. This case highlights the importance of clinical phenotyping as well as comprehensive genetic analysis during genetic testing, including evaluation of synonymous mutations.