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

TL;DR

This study investigates how the parent-of-origin effect influences age of onset in monogenic diseases, specifically applying a new estimation method to ATTRv to improve survival predictions for mutation carriers.

Contribution

The paper introduces an extended method to estimate the parent-of-origin effect on survival in monogenic diseases, validated with simulations and applied to ATTRv family data.

Findings

Parent-of-origin significantly affects survival curves in ATTRv.

The new estimation method accurately captures parent-of-origin effects.

Application demonstrates improved understanding of genetic influence on disease onset.

Abstract

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.