Long-Read Genome Sequencing Could Streamline the Search for Rare Disease Diagnoses

For Immediate Release: Thursday, October 22, 2026, 8:15 a.m. U.S. Eastern Time

Media Contact: Evelyn Mantegani, +1 240-833-2014, [email protected]

Presented By: Lydia Sagath, PhD, Radboud University Medical Center

Rockville, Md. – Diagnosing rare genetic diseases often requires more than 10 separate testing workflows, adding time and complexity to an already difficult diagnostic journey. A prospective study of 1,000 clinical samples found that long-read genome sequencing closely matched standard testing while identifying or refining diagnoses that conventional approaches missed.

Researchers selected the samples to represent almost 300 clinical indications encountered through two medical centers’ annual germline genetic testing. They analyzed each sample using long-read genome sequencing and interpreted the results without knowing the outcomes of standard-of-care testing.

Long-read sequencing produced a conclusive diagnosis for 19.2% of index cases, compared with 16.5% using standard testing. Overall concordance between the approaches was 96.4%. Long-read sequencing improved or refined diagnoses in 28 cases, or 3.4%, primarily by determining whether variants in recessive disease genes were located on the same or different copies of a chromosome. It also detected novel variants that standard testing had missed.

The long-read approach failed to identify two diagnoses found through standard testing. One involved a variant present in only a small proportion of cells, while the other occurred in a region with insufficient sequencing coverage.

Modeling the use of long-read sequencing as an initial test across more than 15,000 cases projected a 2.5-percentage-point increase in diagnostic yield, representing a 15% relative improvement over current practice.

The findings suggest that long-read genome sequencing could eventually combine multiple rare disease tests into a single first-line assay, potentially increasing diagnostic yield and shortening time to diagnosis. Additional implementation studies will be important to assess performance, cost, and feasibility across clinical settings.

About the American Society of Human Genetics (ASHG)

The American Society of Human Genetics (ASHG) is the leading global organization advancing the science of human genetics and genomics. Representing nearly 8,000 researchers, clinicians, genetic counselors, educators, and other professionals, ASHG drives progress in understanding the human genome and its role in health and disease. The Society fosters innovation and collaboration through its flagship events and publications—including the ASHG Annual Meeting and its peer-reviewed journals The American Journal of Human Genetics and Human Genetics and Genomics Advances. ASHG also champions science advocacy, supports the next generation of genetics professionals, and promotes responsible policies and public engagement in genetics. Learn more at www.ashg.org.

Long-Read Genome Sequencing Could Streamline the Search for Rare Disease Diagnoses

Building Blocks of the Genetic Code

Medical Genetics

Human Genetics Scholars Initiative