Genome Sequencing Producing Precise Diagnoses for Range of Rare Diseases

A Swedish study analyzed 5 years’ worth of data from over 3000 patients, 40% of whom received a molecular diagnosis.

Genome sequencing is leading to a large number of diagnoses among patients with rare diseases, says a new study, which is detailing how the method led to more than 12000 individuals with rare diseases receiving a precise diagnosis.

The findings were recently published in Genome Medicine.

The Swedish study analyzed 5 years’ worth of data from over 3000 patients. Of these patients, 40% received a molecular diagnosis. The researchers are calling their work “a major leap forward” in the pursuit of precision medicine. They note that although there are various ongoing large-scale genome sequencing studies around the world, clinical implementation often lags.

"Clinical whole genome sequencing has had huge implications for the area of rare diseases," said Anna Wedell, professor at the Department of Molecular Medicine and Surgery, Karolinska Institute, and one of the study’s corresponding authors, in a statement. "Used in the right way, targeted at each patient's specific clinical situation, new groups of patients can receive the right diagnosis and treatment in a way that hasn't been possible before."

In certain patients, genome sequencing reaped even more benefits, in that it was able to match some patients with personalized treatment. This included patients with inherited metabolic diseases, rare epilepsies, and primary immune deficiencies.

In total, the researchers discovered mutations in more than 750 genes while also uncovering 17 novel disease genes. Some of the most common causative genes were COL2A1 (n = 12; skeletal dysplasia), SCN1A (n = 4; epilepsy), and TNFRSF13B (n = 4; inborn errors of immunity).

Typically, it’s challenging to managing the millions of genetic variants that whole genome sequencing unearths in a patient. To circumvent this, the researchers’ model focuses on the variants considered relevant to an individual patient’s symptoms. The researchers note that this approach calls on doctors to decide which genetic analyses should be done first.

“If the first assessment fails to produce a result, the analysis is broadened to more gene panels until a diagnosis can be established and/or the whole genome is sequenced,” explained the researchers. “This process has also enabled the identification of several previously unknown disease genes, which presents new opportunities for in-depth exploration of pathogenic mechanisms.”


Stranneheim H, Lagerstedt-Robinson K, Magnusson M, et al. Integration of whole genome sequencing into a healthcare setting: high diagnostic rates across multiple clinical entities in 3219 rare disease patients. Genome Med. Published online March 17, 2021. doi:10.1186/s13073-021-00855-5