Expanded carrier screening for assessing reproductive genetic risk in the general population

ESHRE 2020 Fabiani

A study report from Marco Fabiani assessed the value of expanded carrier screening in those trying to conceive in the general population.

Published 09 July 2020

A study of more than 2000 people trying to conceive naturally or by IVF and screened for carrier status of ten genes responsible for inheritable diseases identified 8.6% as carriers and 2.2% of passing on the disease.

The Human Genome Project made possible the identification of heterozygous mutation status (carriers) of more than 2000 autosomal and X-linked recessive disorders in any couple trying to conceive, a process termed population screening. Although theoretically sound, the cost of such screening would prevent mainstream clinical application. Instead, carrier screening (CS) for couples with family history of one of these genetic conditions, has proved a more appropriate approach. If both partners are found to be carriers of the same autosomal recessive disease, or the female is carrier of an X-linked condition, the couple is defined at risk with a 25% chance of conceiving an affected child. Several reproductive options are available to such couples - for example, prenatal screening for natural conceptions or preimplantation genetic testing for monogenic disease (PGT-M) for IVF conceptions.

One of the final sessions of ESHRE’s virtual annual meeting heard Marco Fabiani present work from his team at Igenomix Italia on the utility of extended carrier screening both in the IVF and general population.

Fabiani argued that many couples unaware of their carrier status and trying to conceive might still be at risk of transmitting disease to their child. And for these couples he proposed ‘expanded’ carrier screening (ECS), which involves testing the status of genes responsible for just ten monogenetic diseases as a new cost-efficient alternative to broader population screening.

To test the utility of ECS in the general and IVF population, Fabiani designed a study enrolling 2013 individuals with no history of genetic disease who were trying to conceive naturally or through IVF. Of these individuals 1172 received a ‘combined’ (both partners) ECS and 841 a ‘one-member’ ECS. The application of both strategies identified 8.6% of the tested individuals as carriers for one disease and 2.2% (when the coupe was tested) as at risk of conceiving an affected child. The most common genetic diseases identified were cystic fibrosis followed by spinal muscular atrophy and fragile-X syndrome.

Fabiani emphasised that the study managed to detect three at-risk couples who were trying to conceive spontaneously, highlighting the importance of such knowledge to those couples. In total, the study contributed to the identification of ten couples at risk of having a baby with a genetic disease. He added that all these couples opted for IVF followed by PGT-M, although when asked later about this during the Q&A he argued that prenatal testing might perhaps have been more appropriate. He also acknowledged as limitations ethnic diversity and a limited number of examined genes, though noting consequently that these results might be an underestimation.

Concluding his presentation, Fabiani seemed persuaded of the value of ECS in the detection of at-risk couples in the general population, especially in an era of such fast-moving scientific developments and greater affordability in routine genetic diagnostics. The most popular question coming from the virtual floor was whether a ‘one-member’ ECS strategy might be preferred for general population screening, to which Fabiani answered that a combined test would always generate higher detection rates. With ECS price ranging between $100 and $1000 at the moment, only time will show whether its use will gather popularity among the general public hoping to conceive.

* An ESHRE Ethics Committee has finalised draft recommendations on the ethical implementation of expanded carrier screening in ART patients. The paper is available for stakeholder review on the ESHRE website.

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