Study reveals new insights into genetics of intellectual disability: repetitive DNA

Researchers from the Icahn School of Medicine at Mount Sinai published a study in Genetics of nature This discovery highlights a new genetic variant associated with intellectual abilities and academic achievement. It offers new perspectives on the diagnosis of intellectual disability and on potential therapeutic avenues.

The article is titled “A phenome-wide association study of methylated GC-rich repeats identifies a GCC repeat expansion in AFF3 as an important cause of intellectual disability.”

The study reveals the significant impact of tandem repeats – DNA sequences in which a pattern of nucleotides is repeated multiple times in a head-to-tail fashion on a chromosome – on intellectual functioning.

“The genome contains myriads of these tandem repeats that, when expanded, can disrupt gene function,” said Andrew Sharp, Ph.D., professor of genetics and genome sciences at Icahn Mount Sinai and senior author of the study. “Our research sheds light on how these previously underappreciated genetic features can have a profound impact on human intelligence.”

Tandem repeats can be compared to sentences in the human genome book that are repeated multiple times. An excessive number of these repeats can lead to disruption of genetic instructions, impacting an individual’s development and cognitive abilities, the researchers say.

Using advanced DNA methylation profiling and genotyping, the research team identified a repeat expansion of a specific nucleotide sequence, composed of a series of guanine (G) and cytosine (C) bases followed by another cytosine (C) base (GCC), in the AFF3 gene, which is strongly associated with education level.

This discovery could explain the genetic basis of at least 0.3% of cases of intellectual disability, thus improving the accuracy of genetic testing and diagnosis.

The phenome-wide association approach used in the study, which links genetic variants to human phenotypes, underscores the broader public health implications of these genetic variations. “Identifying AFF3 gene expansion as a contributing factor to intellectual disability is a step toward more accurate and timely diagnoses,” Dr. Sharp noted.

Future research should build on these findings. Although the current study focused on a limited number of tandem repeat expansions, the human genome contains hundreds of thousands of them, many of which are likely to play a role in disease, Dr. Sharp explained.

The team plans to expand their research to further explore these repeated expansions, deepening our understanding of their prevalence and impact on the human population.