Model Developed in Collaboration with Multiple Institutions Applied Clinically… One in Four Patients Diagnosed Within Two Months

When Needed, Linked to Drug Treatment, Organ Transplantation, and Family Planning to Improve Patients’ Quality of Life

▲ (From left) Professor Beom Hee Lee of the Medical Genetics Center at Asan Medical Center, and Director General Hyun-Young Park and Dr. Mi Hyun Park of the National Institute of Health

Since rare genetic diseases affect a small number of patients and have limited related information, making an accurate diagnosis is challenging. Patients often have no choice but to visit multiple hospitals over a period ranging from several months to several years. Recently, to prevent such a “diagnostic odyssey,” Asan Medical Center, in collaboration with the government and domestic medical institutions, developed a multidisciplinary diagnostic model for rare genetic diseases and achieved successful results in clinical practice.

A research team led by Professor Beom Hee Lee of the Medical Genetics Center at Asan Medical Center, together with Director General Hyun-Young Park and Dr. Mi Hyun Park of the National Institute of Health, applied a genome analysis-based multidisciplinary diagnostic model to patients with rare genetic diseases of unknown diagnosis. As a result, one in four patients was able to receive a rapid diagnosis within two months.

To improve the diagnostic rate for rare disease patients, the research team established a diagnostic pipeline based on whole genome sequencing, which analyzes the entire genome and enables close collaboration among physicians, geneticists, genetic counselors, and biologists. This pipeline included not only comprehensive diagnosis through genomic analysis, but also family-based analysis, genetic counseling before and after diagnosis, and subsequent clinical interventions.

The research team then evaluated the clinical effectiveness of the diagnostic model by applying it to 387 undiagnosed patients with rare genetic diseases and 514 family members at eight medical institutions in Korea, including Asan Medical Center, from August to November 2023.

As a result, 27 percent (104 patients) of the participants were able to receive an accurate diagnosis within two months. Among those diagnosed, 77.9 percent were found to have either a single nucleotide variant in their DNA or an insertion or deletion within the DNA sequence. In addition, 40.7 percent were identified as having novel genetic variants that had not been previously reported in medical literature, while 37.3 percent had de novo genetic variants that were not present in either parent but newly occurred in the affected child.

By age group, the diagnostic rate was 30.6 percent in pediatric patients under 18 and 21.5 percent in adult patients over 18, showing a significantly higher rate in children. This is thought to be because many genetic abnormalities manifest relatively early in life.

Patients with a history of genetic testing had a diagnostic rate of 34.9 percent, which was higher than the 20.3 percent observed in patients who had never undergone such testing.

In addition, larger family units showed higher diagnostic rates. When patients underwent genome testing together with their parents and siblings, the diagnostic rate was 70 percent, compared with 15.8 percent when the patient was tested alone. This is likely because including parents or siblings in genome testing increases the likelihood of identifying a genetic disorder.

Among the participating patients, 4.7 percent (18 individuals) were found to have abnormal findings unrelated to their primary condition—the main symptom or disease for which they were originally tested—but which could affect their health in the future.

Based on the results of genomic analysis, the research team provided clinical interventions such as drug treatment, organ transplantation, and counseling for family planning to 150 patients. Among them, 68 patients received specialized genetic counseling, which helped them gain detailed information about their disease as well as improve emotional acceptance and disease management.

Professor Beom Hee Lee of the Medical Genetics Center at Asan Medical Center said, “Through this whole genome sequencing-based multidisciplinary diagnostic model, we were able to identify new genetic variants in patient groups that were difficult to diagnose with conventional single-gene tests or patient-only testing. We also confirmed that genomic analysis can contribute not only to diagnosis but also to treatment decisions and family planning in real clinical settings. If actively applied in clinical practice, it is expected to greatly help improve the quality of life for many patients with rare genetic diseases who face challenges in obtaining a diagnosis.”

The study was recently published in Clinical and Translational Medicine (impact factor 6.9).