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Study Shows 1 Percent of European Couples at Risk of Having Child With Severe Recessive Disorder

NEW YORK – Through an exome sequencing study of two European cohorts, researchers in Europe and Israel have determined the landscape of autosomal-recessive pathogenic variants in European populations, as well as the phenotype-specific effects of those variants in the children of couples from these populations.

Based on 6,447 exome sequences of healthy, genetically unrelated Europeans of two distinct ancestries, the researchers calculated that each individual is a carrier of at least two pathogenic variants in currently known autosomal-recessive (AR) genes, and that about 1 percent of European couples are at risk of having a child affected with a severe AR genetic disorder, they wrote in a paper published on Thursday in the American Journal of Human Genetics.

Further, the researchers found that the risk of having an affected child is 16.5-fold higher for first cousins, and is significantly higher for skeletal disorders and intellectual disabilities because of the distinct genetic architecture of those conditions.

"Europeans carry two to four variants on average. This was suspected before, but this is the first time that we actually see data that proves it," co-corresponding authors and Radboud University Medical Center researchers Christian Gilissen and Hans Brunner said in an email. "More importantly, we now know that 1 percent of non-consanguineous couples are at risk of having children with severe recessive disease. Even though the two populations that we looked at have their own variants, they show striking resemblance in terms of overall carrier frequencies for different disorders."

The researchers used exome sequencing to assess the carrier frequency of AR pathogenic or likely-pathogenic variants (PLPs), the total at-risk-couples (ARCs) rate for various disorders, and the effect of different consanguinity levels on the ARCs rate for these disorders in two European cohorts, from the Netherlands and Estonia.

After various filtering and classification steps to determine the list of possible PLPs, the researchers simulated all possible matings within the 4,120 samples of the Dutch cohort and the 2,327 samples of the Estonian cohort virtually.

Through this, they determined that each Dutch individual, on average, carries 2.3 PLPs for the set of 1,929 AR genes and that each Estonian individual, on average, carries 2 PLPs for the same set of genes. For the subset of 1,119 recessive genes that are associated with severe phenotypes, the mean number of PLPs per individual was 1.5 and 1.1 in the Dutch and Estonian cohorts, respectively.

The virtual matings for the subset of 1,119 severe disease genes yielded 83,878 Dutch and 20,710 Estonian ARCs, leading the researchers to estimate that 0.8 percent to 1 percent of European couples are at risk for a child with a severe AR condition, and at least 1.3 percent to 1.5 percent for a child with any AR condition.

Based on their calculations, the researchers were also able to make other predictions. For example, they said, in the Dutch cohort, metabolic disorders and blindness constitute 79 percent of expected disorders for affected children to non-consanguineous parents, while they make up only 55 percent of affected children to parents who are first cousins. Other phenotypes like intellectual disability and skeletal disorders are expected to be very rare in affected children to non-consanguineous parents, but much more common in children to parents who are first cousins.

Importantly, however, Gilissen and Brunner noted that the data highlighted that heterozygous carriers of recessive diseases are an important source of phenotypic variation.

"The data indicate a paucity of recessive disease alleles for intellectual disability and skeletal diseases compared to other disease classes," they wrote. "This suggests that heterozygous carriers experience enough phenotypic expression to cause a measurable negative selective effect. While such phenotypic effects would likely be quite small at the individual level, their aggregate effect on traits in the population could be considerable."

These analyses revealed the architecture and distribution of AR pathogenic variants throughout the genome and for different disorders, and the results can inform public health policies such as the design of preconception carrier screens and improve preconception counseling, the researchers said.

"For non-consanguineous couples, the risk of recessive disease is largely due to a limited number of genes. Therefore, adding more genes to existing preconception carrier screening (PCS) panels will not substantially increase the PCS yield, for non-consanguineous couples," Gilissen and Brunner said. "In contrast, consanguineous couples will benefit more from an exome-based PCS."

They further noted that the strategies they outlined in the study for curating PLP variants can be applied to any population, and that knowing the types and distribution of genes and disorders can inform carrier screening policies at a national level.