Screening for genetic risk of neurodevelopmental disorder flags just five percent of cases

Genetic testing in most couples reveals just five percent of the genetic risk of their child developing a severe neurodevelopmental disorder.

Whole exome sequencing of 700 parents of children with neurodevelopmental disorders which screened for of all known linked genetic variants, uncovered genetic risk of a disorder just five percent of the time, a study published in npj Genomic Medicine revealed. Current recommendations by the American College of Medical Genetics and Genomics (ACMG) are that couples with no known risk factors, should only be screened for genetic risk variants that are present in over one in 200 individuals in the US population.

As Professor Anita Rauch, the lead author of the study, said: 'Following the US recommendation would more than halve the risk detection rate, because rarer genes also play a part here.'

While targeted screening of parents known to be at higher risk of certain genetic diseases, has been shown to make a difference to the risk of children being conceived with those conditions, less is known about the impact of widening screening to all women who are pregnant or planning to conceive.

'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 to consider prenatal or preimplantation diagnostics,' commented Professor Rauch.

The 350 couples analysed also included 23 couples who were related, for example they were first or second cousins. In these couples, comprehensive screening of all known genetic variants would have identified the risk of the child developing a severe neuromuscular disorder in approximately 44 percent of cases.

Researchers discovered that, on average, each parent carried four disease-causing or likely disease-causing gene variants, with 96.5 percent of the parents screened carrying at least one. This is in line with rates previously predicted, however, the authors highlighted it was predicted up to 6000 autosomal recessive genetic variants that increased risk of neurodevelopmental disorders had not yet been discovered. Therefore the number of pathogenic and likely pathogenic genes each person carries is likely to be significantly more than four.

The authors attributed the low discovery rate of the screening in the non-related couples to the high proportion of neurodevelopmental disorders attributed to gene mutations that appear for the first time in their offspring called de novo mutations. Of the 142 (41 percent) of children in the trial who had received a genetic diagnosis, 63 percent of the children had received a diagnosis related to a de novo gene mutation, which no screening of parents would be able to predict.