Seoul National University Hospital Can Identify Causes in 25 Hours by Testing 56 Genes at Once

Identification of Causative Genes in 12 out of 37 Patients with Undiagnosed Ataxia Using Genomic Analysis
Combined CRISPR-Cas9 and Nanopore Sequencing Reduces Diagnosis from Months to Hours

A diagnostic technology has been developed that can identify the causative gene of ataxia in just 25 hours for patients whose disease origin could not be determined through conventional tests.

A joint research team led by Jeongseop Moon, professor in the Department of Clinical Genomic Medicine at Seoul National University Hospital, and Sangsoo Bae, professor in the Department of Biochemistry at Seoul National University College of Medicine, announced on September 17 that they have developed the "nCATS-STRiker" platform, which analyzes 56 genes associated with repeat expansion disorders in a single test.

From the left: Seonseop Moon and Seungbok Lee, professors in the Department of Clinical Genomic Medicine at Seoul National University Hospital, and Sangsoo Bae, professor in the Department of Biochemistry at Seoul National University College of Medicine. Seoul National University Hospital

Repeat expansion disorders are hereditary diseases caused by abnormally long repetitions of specific sequences within genes, which lead to neurological and other issues. Ataxia is a representative example, and to date, 56 genetic loci have been identified as causes. Using conventional short-read sequencing methods, it has been difficult to clarify the structure and number of long repeats, resulting in diagnostic delays of several months or, in some cases, failure to identify the cause altogether.

The research team applied the "nCATS" technique, which uses the gene-editing CRISPR-Cas9 tool to specifically cut 56 gene loci and then directly reads long DNA sequences with nanopore sequencing. To this, they combined STRiker, a software that automatically analyzes repeat patterns.

By extracting DNA from a patient's blood, the analysis process, including two hours for DNA extraction, five hours for library construction, and 18 hours for sequencing, can be completed within a total of 25 hours.

When applied to 37 patients with undiagnosed ataxia, the team newly identified causative genes in 12 cases (32.4%). Repeat expansion was found in FGF14 in four cases; in ATXN8OS, NOP56, and RFC1, two cases each; and in PRNP and NOTCH2NLC, one case each.

The PRNP repeat expansion reported here is the first such case in Asians. Additional testing in the families of diagnosed patients revealed the same genetic abnormality in six relatives from five families.

The team further explained that this technology enables simultaneous analysis of DNA methylation status. In two families with NOTCH2NLC repeat expansions, the repeat length increased as the gene was passed from mother to child, but increased methylation was also observed, resulting in the absence of symptoms in the children.

Professor Jeongseop Moon said, "This study provides a new diagnostic opportunity for patients with undiagnosed ataxia and other repeat expansion disorders who could not find the cause despite multiple tests. We hope this will enable patients to receive rapid and accurate diagnoses without years of testing." The research results were published in the latest issue of the international journal "Advanced Science."

This content was produced with the assistance of AI translation services.