Journal of Inherited Metabolic Disease

, Volume 41, Issue 6, pp 1159–1167 | Cite as

Molecular genetics of a cohort of 635 cases of phenylketonuria in a consanguineous population

  • Tina Shirzadeh
  • Amir Hossein Saeidian
  • Hamideh Bagherian
  • Shadab Salehpour
  • Aria Setoodeh
  • Mohammad Reza Alaei
  • Leila Youssefian
  • Ashraf Samavat
  • Andrew Touati
  • Mohammad-Sadegh Fallah
  • Hassan Vahidnezhad
  • Morteza Karimipoor
  • Sarah Azadmehr
  • Marzieh Raeisi
  • Ameneh Bandehi Sarhadi
  • Fatemeh Zafarghandi Motlagh
  • Mojdeh Jamali
  • Zahra Zeinali
  • Maryam Abiri
  • Sirous Zeinali
  • Additional individual contributors
Original Article


Phenylketonuria (PKU) is an inborn error of amino acid metabolism caused by mutations in the phenylalanine hydroxylase (PAH) gene, characterized by intellectual deficit and neuropsychiatric complications in untreated patients with estimated frequency of about one in 10,000 to 15,000 live births. PAH deficiency can be detected by neonatal screening in nearly all cases with hyperphenylalaninemia on a heel prick blood spot. Molecular testing of the PAH gene can then be performed in affected family members. Herein, we report molecular study of 635 patients genetically diagnosed with PKU from all ethnicities in Iran. The disease-causing mutations were found in 611 (96.22%) of cases. To the best of our knowledge, this is the most comprehensive molecular genetics study of PKU in Iran, identifying 100 distinct mutations in the PAH gene, including 15 previously unreported mutations. Interestingly, we found unique cases of PKU with uniparental disomy, germline mosaicism, and coinheritance with another Mendelian single-gene disorder that provides new insights for improving the genetic counseling, prenatal diagnosis (PND), and/or pre-implantation genetic diagnosis (PGD) for the inborn error of metabolism group of disorders.


Phenylketonuria Metabolism Consanguinity Genetic counseling 



We would like to thank our colleagues at the National Health Centers throughout the country. Without their referrals this would be incomplete. Our thanks also go to our other colleagues at Dr. Zeinali’s Medical Genetics Lab, KHGRC for doing most of the lab works. We also would like to thank our colleagues at the Genetics Office, Ministry of Health for their advice and support. Last but not least we would like to thank the patients and their families for their sacrifices and giving us their precious blood samples and clinical information. This work was supported financially by KHGRC for which we are grateful.

Additional individual contributors Fatemeh Valizadeh8, Zohreh Sharifi1, Fatemeh Golnabi1, Mehdi Shafaat1.

1Kawsar Human Genetics Research Center, Tehran, Iran.

8Genetics Office, CDC, Ministry of Health of Iran, Tehran, Iran.


Funding was obtained through the Kawsar Human Genetics Research Center in Tehran, Iran.

Compliance with ethical standards

Conflict of interest

T. Shirzad, A. H. Saeidian, H. Bagherian, S. Salehpour, A. Setoodeh, M. R. Alaei, L. Youssefian, A. Samavat, A. Touati, M-S. Fallah, H. Vahidnezhad, M. Karimipoor, S. Azadmehr, M. Raeisi, A. B. Sarhadi1, F. Zafarghandi, M. Jamali, Z. Zeinali1, M. Abiri, and S. Zeinali declare that they have no conflict of interest.

Supplementary material

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Supplementary Fig. 1 Correlation between mutation type and neonatal phenylalanine levels. Neonatal phenylalanine levels in cases in this cohort involved in the newborn screening program were organized by the type of mutation (missense, splicing, nonsense) alleles in this cohort for recurrent mutations. The number of phenylalanine levels represents the number of alleles associated with each phenylalanine level in this cohort. Two-sample T-tests between each mutation type showed a significant difference between alleles associated with missense and splicing mutations (p = .005) and missense and nonsense mutations (p = 0.014). No significant difference was present between splicing and nonsense mutations. Recurrent mutations included in this analysis were mutations 2, 6, 19, 30, 45, 48, 49, 54, 55, 62, 63, 70, and 82 numbered as per Fig. 2. (JPG 3953 kb)
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Supplementary Fig. 2 The most common mutations in PAH in this cohort are shown for each ethnic group included in this study. Up to five most common mutations are shown for each ethnic group if present. (JPG 2375 kb)


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Copyright information

© SSIEM 2018

Authors and Affiliations

  1. 1.Kawsar Human Genetics Research CenterTehranIran
  2. 2.Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical CollegeThomas Jefferson UniversityPhiladelphiaUSA
  3. 3.Genetic, Genomics and Cancer Biology PhD ProgramThomas Jefferson UniversityPhiladelphiaUSA
  4. 4.Department of Pediatric Endocrinology and Metabolism, Mofid Children’s HospitalShahid Beheshti University of Medical SciencesTehranIran
  5. 5.Genomic Research CenterShahid Beheshti University of Medical SciencesTehranIran
  6. 6.Growth and Development Research CenterTehran University of Medical SciencesTehranIran
  7. 7.Department of PediatricsTehran University of Medical SciencesTehranIran
  8. 8.Department of Medical Genetics, School of MedicineTehran University of Medical SciencesTehranIran
  9. 9.Genetics Office, CDCMinistry of Health of IranTehranIran
  10. 10.Drexel University College of MedicinePhiladelphiaUSA
  11. 11.Department of Molecular Medicine, Biotechnology Research CenterPasteur Institute of IranTehranIran
  12. 12.Research Institute for Endocrine ScienceShahid Beheshti University of Medical SciencesTehranIran
  13. 13.Department of cellular and molecular biologyIslamic Azad University North Tehran branchTehranIran
  14. 14.Department of Medical Genetics, School of MedicineIran University of Medical SciencesTehranIran
  15. 15.Department of Molecular Medicine, Biotech Research CenterPasteur Institute of IranTehranIran

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