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Whole-Genome Sequencing Aids Rare Disease Diagnosis in Stockholm-Area Healthcare System

NEW YORK — Incorporating whole-genome sequencing into healthcare around Stockholm has enabled more than 1,000 people with a rare disease to receive a molecular diagnosis, a new study has found.

The Karolinska University Hospital and the Science for Life Laboratory (SciLifeLab) launched the Genomic Medicine Center Karolinska-Rare Disease (GMCK-RD), an academic-clinical partnership, five years ago to offer whole-genome sequencing to individuals with rare diseases with suspected genetic origins.

In that time, researchers at the center have sequenced more than 3,000 patients, leading to molecular diagnoses for about 40 percent of patients, as they reported in Genome Medicine. They uncovered pathogenic mutations in more than 750 genes, and noted both recurrent and novel disease genes that, in some cases, could inform patients' treatment approach, particularly for individuals with metabolic disorders or severe infantile epilepsy.

"Most patients would not have been subjected to genetic investigations with conventional approaches," co-senior author Anna Wedell, a professor of molecular medicine and surgery at the Karolinska Institutet, said in an email. "We have integrated WGS deeply into the clinic, making genomics available in completely new clinical scenarios including acute medical situations across a broad range of disease groups."

In the first five years, the program sequenced the genomes of 3,219 patients. Each patient was referred for WGS following thorough phenotyping, other clinical tests — such as biochemical testing, imaging, and neurophysiological evaluation — and pedigree analysis.

According to the researchers, clinical WGS was gradually implemented at GMCK-RD over the course of five years. At first sequencing was performed on the Illumina HiSeq X Ten, but shifted to the Illumina NovaSeq 6000 in December 2018. Typically, samples were analyzed in a step-wise fashion, in which they were first analyzed for variants associated with the patient's suspected disease — sometimes with very large gene panels of nearly 4,000 genes — before being escalated for additional analysis or whole-genome analysis if no diagnosis was made.

In all, they generated molecular diagnoses for 1,287 patients, or 40 percent, with a median turnaround time of 13 days.

Overall, the researchers uncovered variants in 754 different disease genes, with the most commonly affected genes being COL2A1 and FKRP. A number of variants were also recurrent, some of which were known founder mutations, such as Leu27Ile in FKRP, which was homozygous in 12 people with limb girdle muscle dystrophy, and homozygous expansions in the RFC1 gene among individuals with cerebellar ataxia, neuropathy, and vestibular areflexia syndrome.

Other patients, though, had variants known to arise recurrently as de novo mutations, such as one affecting the PRRT2 gene that leads to seizures.

For some patients having a molecular diagnosis can change their treatment. As the researchers noted, patients with acute-onset inborn errors of metabolism are often treated with glucose infusion, but for patients with pyruvate dehydrogenase deficiency, this can be harmful. Such patients are instead treated with a ketogenic diet.

Wedell added that she thinks WGS will be more widely adopted in the clinic, but that it will require working across disciplines to implement. "Our next step is to work towards new organizational structures to facilitate the required cross-border collaborations," she said. "We will also educate more clinical colleagues so they are familiar with WGS, can aid in patient selection, choice of gene panels, interpretation of findings, and rapid translation into individual care."

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