A deep intronic variant is a common cause of OTC deficiency in individuals with previously negative genetic testing

Pathogenic variants in non-coding regions of genes encoding enzymes or transporters of the urea cycle can lead to urea cycle disorders (UCDs). However, not all commercially available testing platforms interrogate these regions. Here, we used a gene panel based on massively parallel sequencing (MPS) in 10 individuals with clinical or pedigree-based evidence of a proximal UCD but without a molecular confirmation of the diagnosis. We identified causal variant(s) in 5 of 10 individuals, including in 3 of 7 individuals in whom prior molecular testing was unrevealing. We show that a deep-intronic pathogenic variant in OTC, c.540+265G>A, is an important cause of ornithine transcarbamylase (OTC) deficiency.

Automated summary

This study utilized a gene panel based on massively parallel sequencing to test 10 individuals with clinical or pedigree-based evidence of proximal UCD without molecular confirmation, identifying causal variants in 5 of the individuals. The findings suggest that deep-intronic pathogenic variants may play an important role in causing OTC deficiency.