A study carried out by the University of Helsinki (Finland) has shown that the risk of recurrence of intellectual disability in the next child in each family is usually low, which indicates that it is rarely inherited. The study, published in the journal Human Genetics, used exome sequencing to determine the possible genetic background of intellectual disability. The study participants were Finnish families with family members with delayed cognitive development for which no clear cause had been identified.
A known gene for intellectual disability was found to be caused by a known gene for intellectual disability in 64 percent of the study participants. The majority of these variants, 75 percent, were the result of random mutations that occurred during fetal development (de novo), and variants that were not found in the parental genome. An inherited mutation was identified in no more than a quarter of the pathogenic genes studied. Larger structural variants, which are not normally inherited, were found in only 8 percent of families.
The prevalence of intellectual disability, that is, difficulties in learning and understanding new things, is approximately 1-2 percent of the population. People with a severe intellectual disability need help from others in daily activities throughout their lives. These disabilities can be caused by genetic changes or external factors. According to estimates, some 2,500 genes underlie intellectual disability, of which about half remain unidentified.
In recent years, the diagnosis of intellectual disability has improved thanks to advances in techniques for sequencing the entire genome. These techniques can also help identify causes of intellectual disability that are not found in other medical examinations and tests.
Exome sequencing, that is, the sequencing of protein-coding regions of the genome, also makes it possible to identify new pathogenic genetic variants. Identification of genes is a prerequisite for identifying disease mechanisms and developing treatments.
The technique enables the cause of disability to be investigated faster than before, alleviating uncertainty and concern for families, as well as generating savings in health care. “The more we understand the factors underlying intellectual disability and its hereditary nature, the better we can help families dealing with these serious disorders,” explains one of the authors, Irma Järvelä.
Distant family connections
The Finnish population is known for its severe recessive inherited diseases caused by single gene defects, known as founder variants, of which about 40 are known so far. This work has shown that the variants created in early fetal development are the most common cause of intellectual disability also in the Finnish population. Known variants associated with recessive diseases were identified in only 5 percent of the families included in the study, a result in line with other European populations.
“Despite the isolation of our population, Finns do not differ from other European populations in the inheritance of intellectual disability,” says Järvelä. A distant family connection dating back 7-10 generations reduces risk to establish a recessive inherited disease even in small populations.
The study identified nine new candidate genes, of which a handful turned out to be recessive. In further research, one of these genes could turn out to be a hitherto unknown gene enriched in the Finnish population.