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