Rare Daily Staff

Pacific Biosciences of California and Rady Children’s Institute for Genomic Medicine are collaborating on a study that seeks to identify potential disease-causing genetic variants to improve the diagnosis of rare diseases.

The study is making use of long-read whole genome sequencing of undiagnosed rare disease patients for whom short-read whole genome and exome sequencing failed to yield answers. The study, which is currently underway, has already been able to detect variants that were not identified by short-read sequencing (SRS). Of these newly found variants, an average of 37 were so-called “missense” mutations in known disease genes. Missense mutations involve the change of a single base pair that results in the substitution of an amino acid in the protein for which a gene codes and can render it non-functional.

“PacBio HiFi sequencing can identify numerous variants, both small and structural that are not readily detectable by SRS,” said Matthew Bainbridge, principal investigator, and associate director of clinical genomics at Rady Children’s Institute for Genomic Medicine.

In rare disease studies, conventional techniques for whole-genome and whole-exome analysis based on SRS typically led to identification of a causal variant in less than 50 percent of cases. Utilizing PacBio’s Single Molecule, Real-Time (SMRT) Sequencing technology to generate highly accurate long-reads, known as HiFi reads, clinical researchers have demonstrated that they can detect disease-causing structural and small variants missed by short-read sequencing platforms. This study is designed to evaluate the rate at which HiFi sequencing identifies overlooked causal variation.

“We’ve been aware that there’s a subset of seriously ill babies and children who don’t receive a diagnosis with current sequencing methods, but based on their symptoms, we’re fairly certain that they have an underpinning genetic disease,” said Stephen Kingsmore, president and CEO of Rady’s Children’s Institute for Genomic Medicine. “With this new technology, we are excited to see how many more of these children and families will receive additional insight regarding the identification of potential disease-causing genetic variants.”

Photo: Stephen Kingsmore, president and CEO of Rady’s Children’s Institute for Genomic Medicine

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