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Despite significant advancements in genetic testing, over half of individuals worldwide with suspected Mendelian genetic disorders still lack an accurate molecular diagnosis. Many others undergo extensive testing over several years before receiving a diagnosis. Researchers at King Abdullah University of Science and Technology (KAUST) and other institutions across Saudi Arabia have now developed NanoRanger, a method that promises to deliver accurate genetic diagnoses within hours.
Addressing the Need for Precise Genomic Diagnosis
"Precise, efficient genomic diagnosis is urgently needed to improve patient outcomes and facilitate carrier screening," explains Yingzi Zhang, a Ph.D. candidate at KAUST supervised by Mo Li. This development aligns with Saudi Arabia’s Vision 2030, which aims to advance healthcare through innovation to enhance the quality of life for all citizens.
Mendelian disorders, including various nervous system and intellectual developmental conditions, result from specific gene alterations or abnormal genome segment rearrangements. Each disease is associated with a distinct "breakpoint," the genomic location where structural variants such as deletions, rearrangements, or inversions occur.
Traditional screening techniques can identify these variants, but the complexity of the rearrangements often results in missed diagnoses. This issue is particularly acute in regions where consanguinity is common, as inheritable diseases are more prevalent when both parents are carriers of the same faulty segment.
NanoRanger's Innovative Approach
"NanoRanger uses simple molecular biology strategies to 'fish out' genomic regions suspected of harboring complex mutations, deletions, or rearrangements," says Mo Li. This technique is cost-effective and requires only a small amount of DNA from a patient or suspected carrier.
The process begins with the fragmentation of genomic DNA using restriction enzymes, producing pieces with identical end sequences. These fragments are then self-joined into circles and amplified, facilitating the targeting and sequencing of genomic regions of interest using Oxford Nanopore Technologies' long-read sequencing technology.
"Using our custom-developed data analysis tool, NanoRanger accurately maps breakpoints at single base-pair resolution, providing a detailed picture that helps diagnose the genetic disorder," Zhang notes. "Diagnosis can be as fast as 12 minutes after initial sequencing, which is a game-changer."
Successful Trials and Future Applications
In collaboration with Saudi clinicians led by Fowzan Alkuraya at King Faisal Specialist Hospital & Research Center, NanoRanger was tested in 13 familial cases of genomic disorders previously missed by conventional genetic tests. The technique successfully identified precise breakpoints, enabling the screening of carrier status among related family members and 1,000 healthy Saudi individuals.
One Saudi couple participating in the trial opted for in vitro fertilization after both were found to carry the genomic deletion responsible for an inherited Mendelian disease.
"We have filed for a patent and plan to integrate NanoRanger into standard diagnostic routines to provide a comprehensive toolkit for clinical settings, both here in Saudi Arabia and across the world," Li concludes.
Original Publication
Zhang, Y., Bi, C., Nadeef, S., Maddirevula, S., Alqahtani, M., Alkuraya, F. S., & Li, M. (2024). NanoRanger enables rapid single-base-pair resolution of genomic disorders. Med, 3(7). https://doi.org/10.1016/j.medj.2024.07.003