Genetic testing for pregnancy detects up to 50% of the risk

The use of biomarkers and genetic testing during pregnancy is now very widespread. But what if the parents’ genes were analyzed extensively for potential risks before conception? Are there any rare genetic diseases in the genome that are unintentionally carried by the father and/or mother? If both parents have the same genetic defect in their genes and both pass this on to their child, it often causes the child to become seriously ill.

In many parts of the United States, broad-based genetic testing is offered to prospective parents and is also recommended in early pregnancy. The tests mostly point to recessive genetic genes that do not belong to a gender – in other words, those that only have an effect if both genetic copies carry a mutation. Recessive genes on the X chromosome are a special case, since healthy mothers can pass this gene on to their children. However, sons usually only suffer the consequences of this mutation because they carry one X chromosome and therefore do not have a second gene copy to compensate for the defect.

More than 3000 genetic factors have been tested

Do these genetic tests for inherited risk factors deliver what they promise? Anita Rauch, director of medical genetics at the University of Zurich, and her team in Switzerland have addressed this question for the first time by extensively studying the potential and risks of such an expanded carrier screening (ECS). To this end, the scientists tested sequencing data from 700 parents who already had children with neurodevelopmental disorders. Many of the more than 3,000 genes examined can cause intellectual disabilities, developmental disorders, autism, and other disorders.

“In our study, we were able to show that this type of broad genetic testing can detect a child’s risk of a severe developmental disorder in about 44 percent of cases if the parents are blood related – eg as first or second cousins,” says Anita. Rauch. This is common in some population groups, for example in the Middle East or North Africa.

Gaps in risk disclosure for unrelated spouses in particular

The test still detects about 5 percent of cases in couples who were not related by blood — but only if all known recessive genes are investigated. According to recommendations in the United States, only unrelated pairs should be tested for common genes that are known to have a certain carrier frequency in the population. “Following the US recommendation would halve the risk detection rate, because rare genes also play a role here,” Rauch explains.

For children of non-relative couples, a much higher proportion of developmental disorders are due to non-inherited de novo mutations, while in children of related parents, genetic defects play a clearly greater role. For this reason, the researchers report that the probability of detecting risk by analyzing the parents’ genes is limited for unrelated couples.

Many disease-causing genes are still undiscovered

Other factors also influence the potential of these tests to detect problematic genetic variants in known disease-causing genes: in particular, missense gene mutations, in which the genetic blueprint may or may not be altered, and inherited copy number variants, in which the number of copies of genes is Incorrect, it has been underestimated. Undetectable cases are those in which a genetic defect and a newly acquired one occur at the same time.

In addition, there are likely several thousand genes that have not yet been identified that are likely to also cause developmental disorders. For example, in the study group examined, the cause of the developmental disorder in the children involved remained unknown in about 58 percent of cases.

A conscious decision for or against children

However, according to the researchers, the study provides data on the feasibility of expanded carrier screening. Based on the high risk detection rate of consanguineous parents, the researchers believe that such a screening should definitely be offered to these couples. In all other cases, the benefits and drawbacks should be evaluated 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 to have children together or consider a prenatal or pre-implantation diagnosis,” Rauch says.

However, the results also show that potential risk reduction is strongly dependent on the genes identified and the variable ratings in the test. According to Rauch, there is still potential for improvement in the tests currently offered: “To improve clinical utility, all couples who want broad genetic testing to screen all recessive genes should be considered regardless of population prevalence of the gene variant. Laboratories should also use reasonable thresholds in relation to time. in which the genetic defect is considered pathogenic.”

Reference: Bonsawat F, Horn AC, Stindel K, et al. Assessment of the clinical utility of expanded preconception of carrier screening in relation to residual risk for neurodevelopmental disorders. npj genome med. 2022; 7 (1): 1-12. dui: 10.1038 / s41525-022-00316-x

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