Genetic screening before pregnancy detects risk in 44% of couples

More than 3,000 hereditary factors tested

Do these genetic tests for hereditary risk factors keep their promises? Anita Rauch, head of the Department of Medical Genetics at the University of Zurich, and her team in Switzerland have for the first time answered this question by thoroughly investigating the potential and pitfalls of this expanded carrier screening (ECS). To this end, the scientists tested sequence data from 700 parents who had previously had children with neurodevelopmental disorders. Of the more than 3,000 genes studied, many can cause intellectual disabilities, developmental disabilities, autism and other disorders.

In our study, we were able to show that this type of broad genetic test can detect the risk of the child suffering from a serious developmental disorder in around 44% of cases if the parents are related by blood – for example as than first cousins ​​or second cousins. »

Anita Rauch, head of the department of medical genetics at the University of Zurich.

In some population groups, this situation is quite common, for example, in the Middle East or North Africa.

Gaps in risk detection for non-consanguineous couples in particular

The test still detected around 5% of cases in couples who were not related by blood – but only if all known recessive genes were examined. However, according to American recommendations, non-consanguineous couples should only be tested for common genes which are known to be carriers at a certain frequency in the population. “Following the US recommendation would more than halve the risk detection rate, as rarer genes also play a role here,” says Rauch.

In children of non-consanguineous couples, a significantly higher proportion of developmental disorders are caused by non-hereditary diseases. Again whereas in children of related parents, inherited genetic defects play a significantly greater role. For this reason, the researchers say that the likelihood of detecting risk by analyzing parental genes is limited for non-consanguineous couples.

Many pathogenic genes are still undetected

Other factors also affect the ability of these tests to detect problematic genetic variants in known pathogenic genes: in particular, missense gene mutations, in which the genetic blueprint may or may not be altered, and variants Inherited copy number genes, in which the gene copy number is incorrect, have been underestimated. Cases that cannot be detected are usually those in which an inherited genetic defect and a newly acquired genetic defect occur at the same time.

In addition, there are probably several thousand as yet unidentified genes that also cause developmental disorders. For example, in the cohort studied, the cause of the developmental disorder in the children concerned remained unexplained in approximately 58% of cases.

Conscious decision for or against children

Nevertheless, according to the researchers, the study provides data on the importance of expanded carrier screening. Based on the high rate of detection of risk in consanguineous relatives, the researchers believe that this screening should certainly be offered to these couples. In all other cases, the pros and cons should be weighed on a case-by-case basis to avoid creating unrealistic expectations. “If a couple is found to be at risk of having children with neurodevelopmental disorders, they will be fully aware and able to decide whether or not they want to have children together or consider prenatal diagnosis or preimplantation,” says Rauch.

However, the results also show that the potential risk reduction is highly dependent on the genes selected and the variant classifications in the test. According to Rauch, there is still potential for improving the tests currently offered: “To improve clinical benefit, consideration should be given to subjecting all couples who want a broad genetic test to screening for all recessive genes, regardless of prevalence. of a genetic variant in the population. Laboratories should also use reasonable thresholds for when a genetic defect is considered pathogenic. »