Whole-genome sequencing can be used to diagnose intellectual disability more accurately than other methods of genetic analysis, according to researchers at the Karolinska Institute. Using analytical tools developed by the researchers, whole-genome sequencing is now being introduced for first-line clinical diagnosis at the Karolinska University Laboratory.
“Recent technical leaps in genetic diagnostics have revealed many new genetic aberrations that cause intellectual disability,” says Anna Lindstrand, MD, PhD, associate professor at the Karolinska Institute and clinical genetics specialist at Karolinska University Hospital. “Given that there are currently over 800 different diagnoses described in the literature, making a diagnosis can be a time-consuming process.”
An estimated 1.5% of the Swedish population has some sort of intellectual disability, caused in most cases by genetic aberrations ranging from small point mutations (one or a few base pairs) in individual genes, or a few base-pair repetitions, to larger structural chromosome mutations comprising one or more genes.
Most individuals with an intellectual disability are offered a clinical examination using so-called gene dose array and DNA analysis for fragile X syndrome. Such genetic tests produce a molecular causal diagnosis in about 12% of cases, for which physicians can order further analytical tests ranging from individual genes to the entire genome (whole-genome sequencing).
In the recent study, the researchers developed their own analytical tool, which, in combination with whole-genome sequencing, discovers point mutations, structural chromosome aberrations, and repetitions (expansions).
Conducting parallel gene dose array tests and whole-genome sequencing for 100 individuals, the researchers were able to show that more than twice as many patients (27%) could obtain a causal diagnosis with whole-genome analysis compared with the array technique.
“In just a short space of time, whole-genome sequencing has become inexpensive enough to be used as an all-round test for finding different genetic mutations,” says Lindstrand. “The cost of sequencing a person’s entire genome is now just marginally higher than other genetic analyses currently employed to find genetic mutations.”
Karolinska University Laboratory will be one of the first clinical laboratories in the world to introduce whole-genome sequencing as a first-line clinical diagnostic tool for intellectual disability.
- Lindstrand A, Eisfeldt J, Pettersson M, et al. From cytogenetics to cytogenomics: whole-genome sequencing as a first line test comprehensively captures the diverse spectrum of disease-causing genetic variation underlying intellectual disability. Genome Med. 2019;11(1):68; doi: 10.1186/s13073-019-0675-1.