A recent study from researchers at Baylor College of Medicine has demonstrated the significant advantages of ultra-deep RNA sequencing for diagnosing Mendelian disorders. Published in the American Journal of Human Genetics, this research highlights how increasing sequencing depth can improve clinical diagnostics, particularly for low-abundance transcripts and rare splicing events that are crucial in interpreting gene variants.
Most existing RNA sequencing diagnostic protocols utilize moderate sequencing depths, typically between 50 million and 150 million reads. Such depths can miss critical genetic variations that have significant clinical implications. The team from Baylor aimed to explore the diagnostic potential of ultra-high depth RNA sequencing, achieving depths of up to 1 billion reads.
Dr. Pengfei Liu, the study’s corresponding author and director of the Medical Genetics Multiomics Laboratory (MGML) at Baylor, stated, “Using the Ultima Genomics ultra-high depth RNA-seq platform, we substantially increased the detection of lowly expressed genes and transcripts.” This enhanced capability allows for the evaluation of many more low-expression genes that traditional sequencing methods might overlook.
In clinical diagnostics, identifying low-expression genetic variants is essential. Blood and skin samples are most commonly tested, but genes linked to developmental and neurological disorders often exhibit low expression in these tissues. Dr. Liu emphasized the implications of their findings, saying, “If you can sequence blood samples to extremely high depths, you can capture those genes traditionally thought to be tissue specific.”
The findings from this study pave the way for further advancements in RNA sequencing research. The Baylor team has developed an online resource that estimates the necessary sequencing depth required to achieve a genetic diagnosis. This tool also predicts pathogenic abnormal gene splicing based on deeply sequenced data from healthy individuals.
Moving forward, the researchers plan to validate their ultra-deep RNA sequencing approach clinically and aim to create a test based on their findings. “In the MGML, we are leaders in translating new genomic technologies into real-world clinical practice,” Dr. Liu added. “We continue to evaluate new technology that can help improve diagnostic rates for our patients.”
The study involved significant contributions from various researchers including Sen Zhao, Jefferson C. Sinson, Shenglan Li, and others, all affiliated with Baylor College of Medicine, Ultima Genomics, and Baylor Genetics. This work was conducted in collaboration with the Undiagnosed Diseases Network and received support from the National Institute of Neurological Disorders and Stroke and the National Human Genome Research Institute.
As the field of genomics continues to evolve, this study represents a crucial step in enhancing diagnostic capabilities for Mendelian disorders, ultimately benefiting patients and healthcare providers alike.
