Long read sequencing enhances pathogenic and novel variation discovery in patients with rare diseases

Shruti Sinha (), Fatma Rabea, Sathishkumar Ramaswamy, Ikram Chekroun, Maha El Naofal, Ruchi Jain, Roudha Alfalasi, Nour Halabi, Sawsan Yaslam, Massomeh Sheikh Hassani, Shruti Shenbagam, Alan Taylor, Mohammed Uddin, Mohamed A. Almarri, Stefan Du Plessis, Alawi Alsheikh-Ali and Ahmad Abou Tayoun ()
Additional contact information
Shruti Sinha: Dubai Health
Fatma Rabea: Dubai Health
Sathishkumar Ramaswamy: Dubai Health
Ikram Chekroun: Dubai Health
Maha El Naofal: Dubai Health
Ruchi Jain: Dubai Health
Roudha Alfalasi: Dubai Health
Nour Halabi: Dubai Health
Sawsan Yaslam: Dubai Health
Massomeh Sheikh Hassani: Dubai Health
Shruti Shenbagam: Dubai Health
Alan Taylor: Dubai Health
Mohammed Uddin: Dubai Health
Mohamed A. Almarri: Dubai Health
Stefan Du Plessis: Dubai Health
Alawi Alsheikh-Ali: Dubai Health
Ahmad Abou Tayoun: Dubai Health

Nature Communications, 2025, vol. 16, issue 1, 1-7

Abstract: Abstract With ongoing improvements in the detection of complex genomic and epigenomic variations, long-read sequencing (LRS) technologies could serve as a unified platform for clinical genetic testing, particularly in rare disease settings, where nearly half of patients remain undiagnosed using existing technologies. Here, we report a simplified funnel-down filtration strategy aimed at enhancing the identification of small and large deleterious variants as well as abnormal episignature disease profiles from whole-genome LRS data. This approach detected all pathogenic single nucleotide, structural, and methylation variants in a positive control set (N = 76) including an independent sample set with known methylation profiles (N = 57). When applied to patients who previously had negative short-read testing (N = 51), additional diagnoses were uncovered in 10% of cases, including a methylation profile at the spinal muscular atrophy locus utilized for diagnosing this life-threatening, yet treatable, condition. Our study illustrates the utility of LRS in clinical genetic testing and the discovery of novel disease variation.

Date: 2025
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DOI: 10.1038/s41467-025-57695-9

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