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Clinical Application of Next Generation Sequencing for Mendelian Disease Diagnosis in the Iranian Population Publisher



Abolhassani A1 ; Fattahi Z1 ; Beheshtian M1 ; Fadaee M1 ; Vazehan R1 ; Ahangari F1 ; Dehdahsi S1 ; Faraji Zonooz M1 ; Parsimehr E1 ; Kalhor Z1 ; Peymani F1 ; Mozaffarpour Nouri M1 ; Babanejad M3 ; Noudehi K1 Show All Authors
Authors
  1. Abolhassani A1
  2. Fattahi Z1
  3. Beheshtian M1
  4. Fadaee M1
  5. Vazehan R1
  6. Ahangari F1
  7. Dehdahsi S1
  8. Faraji Zonooz M1
  9. Parsimehr E1
  10. Kalhor Z1
  11. Peymani F1
  12. Mozaffarpour Nouri M1
  13. Babanejad M3
  14. Noudehi K1
  15. Fatehi F1
  16. Zamanian Najafabadi S1
  17. Afroozan F1
  18. Yazdan H1
  19. Bozorgmehr B1
  20. Azarkeivan A1
  21. Sadat Mahdavi S4
  22. Nikuei P5, 6
  23. Fatehi F1
  24. Jamali P8
  25. Ashrafi MR9
  26. Karimzadeh P10
  27. Habibi H11
  28. Kahrizi K3
  29. Nafissi S7
  30. Kariminejad A1
  31. Najmabadi H1
Show Affiliations
Authors Affiliations
  1. 1. Kariminejad - Najmabadi Pathology & amp
  2. 2. Genetics Center, Tehran, Iran
  3. 3. Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
  4. 4. Genetic Clinic of Tehran Welfare Organization, Tehran, Iran
  5. 5. Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
  6. 6. Nasle Salem Genetic Counseling Center, Bandar Abbas, Iran
  7. 7. Department of Neurology, Neuromuscular Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
  8. 8. Genetic Counseling Center, Shahroud Welfare Organization, Semnan, Iran
  9. 9. Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
  10. 10. Pediatric Neurology Department, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  11. 11. Hamedan University of Medical Science, Hamedan, Iran

Source: npj Genomic Medicine Published:2024


Abstract

Next-generation sequencing (NGS) has been proven to be one of the most powerful diagnostic tools for rare Mendelian disorders. Several studies on the clinical application of NGS in unselected cohorts of Middle Eastern patients have reported a high diagnostic yield of up to 48%, correlated with a high level of consanguinity in these populations. We evaluated the diagnostic utility of NGS-based testing across different clinical indications in 1436 patients from Iran, representing the first study of its kind in this highly consanguineous population. A total of 1075 exome sequencing and 361 targeted gene panel sequencing were performed over 8 years at a single clinical genetics laboratory, with the majority of cases tested as proband-only (91.6%). The overall diagnostic rate was 46.7%, ranging from 24% in patients with an abnormality of prenatal development to over 67% in patients with an abnormality of the skin. We identified 660 pathogenic or likely pathogenic variants, including 241 novel variants, associated with over 342 known genetic conditions. The highly consanguineous nature of this cohort led to the diagnosis of autosomal recessive disorders in the majority of patients (79.1%) and allowed us to determine the shared carrier status of couples for suspected recessive phenotypes in their deceased child(ren) when direct testing was not possible. We also highlight the observations of recessive inheritance of genes previously associated only with dominant disorders and provide an expanded genotype–phenotype spectrum for multiple less-characterized genes. We present the largest mutational spectrum of known Mendelian disease, including possible founder variants, throughout the Iranian population, which can serve as a unique resource for clinical genomic studies locally and beyond. © The Author(s) 2024.
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