Improving personalised genetic counselling for ABCA4-associated retinopathy: Updated recurrence risk estimates

TL;DR

This paper updates recurrence risk estimates for a genetic eye disease called Stargardt disease by considering factors like ancestry and missing heritability.

Contribution

The paper introduces a more comprehensive model for recurrence risk by incorporating missing heritability and reduced penetrance.

Findings

Not all variant combinations in ABCA4 cause disease, complicating recurrence risk estimation.

Previous estimates overrepresented white patients and assumed independence from genetic ancestry.

New factors like de novo variants and reduced penetrance are now considered in risk calculations.

Abstract

Stargardt disease type 1 (STGD1) is caused by biallelic pathogenic variants in ABCA4. These variants vary in their effect on the resulting protein and the disease phenotype. Not all variant combinations cause disease, which complicates the determination of the recurrence risk of STGD1. Previously, the recurrence risk of STGD1 was estimated by analyzing variants in patient data and using their population variant frequencies in which white patients are overrepresented. Furthermore, assuming that variant effects are independent of genetic ancestry, estimates were made for each gnomAD population. In this article, the effects of missing heritability, de novo variants, reduced penetrance of variants and sex/gender are incorporated and discussed.

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