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Estonian Population Profiling Reveals Recurrent, Rare CNVs Linked to Intellectual Ability

NEW YORK (GenomeWeb) – An international team led by investigators in Switzerland has shown that both syndrome-associated copy number variants and rare CNVs affecting intellectual capabilities can turn up quite frequently in a population of individuals not selected for any particular clinical conditions.

As they reported online today in the Journal of the American Medical Association, the researchers did array-based copy number variant profiling on thousands of randomly selected individuals from an Estonian population biobank. Their results revealed dozens of individuals with copy number variants that have been linked to cognitive, psychiatric, or other syndromes.

Hundreds more carried rare autosomal deletions or duplications, the team noted, including some CNVs suspected of predisposing carriers to intellectual disability or lower-than-usual educational attainment.

Based on their findings in the Estonian population, the researchers, led by corresponding author Alexandre Reymond, a researcher with the University of Lausanne's Center for Integrative Genomics, noted that "individually rare but collectively common intermediate-size CNVs may be negatively associated with educational attainment."

Reymond and his colleagues drew from the Estonian Genome Center-University of Tartu (EGCUT) population biobank with the aim of characterizing contributions that CNVs make to genetic variation in an unselected population. The EGCUT collection includes samples from some 52,000 individuals, they noted, paired with self-reported health and lifestyle traits.

For the discovery stage of the study, the team did array-based CNV profiling on more than 7,000 of these individuals, followed by replication testing on nearly 1,100 more.

Following their quality control steps, the researchers were left with CNV data for 7,877 individuals from the discovery and replication groups. Of those, 56 individuals carried CNVs signifying autosomal syndromes ranging from cognitive or neuropsychiatric conditions to epilepsy or obesity.

Another 831 individuals — just over 10 percent of those tested — carried other forms of rare, autosomal CNVs. There, the team found that duplications were more common than deletions: In the discovery group, for example, 509 of 6,819 individuals had duplications spanning at least 250,000 bases, while just 216 carried rare autosomal deletions in that size range.

On the other hand, even modestly large deletions appeared to increase the incidence of intellectual disability. The team noted that more than 5 percent of those with rare, autosomal deletions larger than 250,000 bases showed signs of intellectual disability — compared with 1.7 percent of individuals in the EGCUT population at large.

Similarly, cognitive problems turned up in six of the 102 individuals with large duplications, but only when those duplications spanned at least one million bases or more.

When they dug into these findings a bit more, the investigators learned that individuals with rare autosomal deletions larger than 250,000 bases or rare autosomal duplications than encompassed more than a million bases were also less likely to have finished high school than were individuals in the general population in Estonia.

The study's authors saw similar results in follow-up analyses on other individuals from Estonia and elsewhere, prompting them to propose that "both recurrent syndromic and rare intermediate-size non-recurrent CNVs, which are cumulatively frequent in the general population, are associated with intellectual disability and negatively with educational attainment.

Baylor College of Medicine and Texas Children's Hospital researcher James Lupski discussed the findings in a related editorial article set to appear in the same issue of JAMA. 

Lupski noted that "[u]nderstanding the specific biological systems involved and how their perturbation results in reduced intellectual abilities including cognitive performance, will better characterize the molecular etiology and the potential cause for the susceptibility to intellection disability and other neurocognitive traits observed as well as provide insights into any other possibly associated disease processes."

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