Study of the parent-of-origin effect in monogenic diseases with variable age of onset. Application on ATTRv

In genetic diseases with variable age of onset, an accurate estimation of the survival function for the mutation carriers and also modifying factors effects estimations are important for the management of asymptomatic gene carriers across life. Among the modifying factors, the gender of the parent transmitting the mutation (i.e. the parent-of-origin effect) has been shown to have a significant effect on survival curve estimation on transthyretin familial amyloid polyneuropathy (ATTRv) families. However, as most genotypes are unknown, the parent-of-origin must be calculated through a probability estimated from the pedigree. We propose in this article to extend the method providing mutation carrier survival estimates in order to estimate the parent-of-origin effect. The method is both validated on simulated data and applied to familly samples with ATTRv.

Automated summary

In genetic diseases with variable age of onset, accurate estimation of the survival function for mutation carriers and understanding the effects of modifying factors, such as parent-of-origin, is crucial for managing asymptomatic gene carriers. This article proposes a method to estimate the parent-of-origin effect and provides survival estimates for mutation carriers using simulated data and real samples from familial cases of ATTRv.