Combining clinically benign IDUA variants in cis reduces enzymatic activity of the resulting enzyme within the pathogenic range

Abstract

Interpretation of genotypes with multiple variants can be challenging as independent effects of each variant must be determined to predict the overall outcome for biallelic conditions. This is especially difficult when two or more variants exist in cis on a single allele. We used an established functional platform to characterize the impact of different clinically benign IDUA variants alone, or in combination, demonstrating that the relative specific activity of in cis variant combinations is comparable to individual variants associated with attenuated or even severe MPSI. These results reinforce the concept that combinations of otherwise clinically benign variants can produce pathogenic consequences.