iPREGCARE: impact of Personalised Genetic Counselling for couples with a child affected by a disorder caused by a de novo mutation

Genetic diagnoses for severe pediatric disorders caused by new genetic variants, known as de novo mutations (DNM), affect approximately 3,500 births in the UK each year.

This number is greater than the total cases of trisomies 13, 18, and 21 combined, for which genetic screening is routinely available.

When a child is diagnosed with a condition due to a DNM, it often brings significant psychological and practical challenges for parents, who are eager to understand the risk of their future children having the same condition ( the recurrence risk ).

Our research aims to understand how parents of a child with a DNM-related condition perceive reproductive risks and their opinions on the potential benefits and drawbacks of general and personalised risk assessments.

Currently, healthcare professionals inform parents that there is a 1-2% chance of the DNM recurring in a future pregnancy.

However, this 1-2% figure is a population average estimate which is imprecise and does not reflect the actual risk to individual couples.

The majority of couples have a negligible risk but current provision does not distinguish them from those with a significantly higher recurrence risk, which happens when the DNM is present in multiple gonadal cells (sperm or eggs) of one parent ( mosaicism ).

The 1-2% generic risk is often difficult to interpret, making it hard for couples to make informed decisions about future pregnancies, potentially causing them to either avoid pregnancy altogether or undergo risky prenatal tests.

Others might interpret the risk as low and plan a pregnancy, not realising their individual risk is actually much greater.

We have previously developed a systematic testing strategy called PREGCARE (PREcision Genetic Counselling And REproduction) which provides a more accurate and personalised recurrence risk estimate prior to a new pregnancy.

This novel method uses Deep-Sequencing and haplotyping of multiple biological samples to establish the likely origin of the DNM by determining whether germline and/or somatic mosaicism can be detected in a family member, thus establishing the recurrence risk for a future pregnancy.

Our aim is to gather evidence for the effective clinical translation of this technology by exploring (a) how personalised risk information affects parents' reproductive decision-making and (b) the best ways to communicate this risk information to them. In this 20-month study, we will conduct one-hour interviews with couples and collect qualitative data.

We will use thematic analysis, a flexible, widely used method for analysing textual data that is not bound to a specific theoretical framework, to scrutinise the data.

Along with academic articles, we plan to work with our Patient Advisory Group (PAG) to co-create an infographic resource to communicate up-to-date knowledge on DNMs and mosaicism.

This complex and rapidly developing area of research can be challenging for health professionals and the public to understand.

This project will be part of a set of recommendations (portfolio) aiming at providing personalised risk assessment (PREGCARE) and will support the process of translating and integrating this research into the NHS Genomic Test Directory.