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J Inherit Metab Dis. 2018 Nov;41(6):1159-1167. doi: 10.1007/s10545-018-0228-6. Epub 2018 Aug 29.

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

Author information

1
Kawsar Human Genetics Research Center, 41 Majlesi St., Vali Asr St., Tehran, 1595645513, Iran.
2
Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA.
3
Genetic, Genomics and Cancer Biology PhD Program, Thomas Jefferson University, Philadelphia, PA, USA.
4
Department of Pediatric Endocrinology and Metabolism, Mofid Children's Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
5
Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
6
Growth and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran.
7
Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran.
8
Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
9
Genetics Office, CDC, Ministry of Health of Iran, Tehran, Iran.
10
Drexel University College of Medicine, Philadelphia, PA, USA.
11
Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
12
Research Institute for Endocrine Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
13
Department of cellular and molecular biology, Islamic Azad University North Tehran branch, Tehran, Iran.
14
Department of Medical Genetics, School of Medicine, Iran University of Medical Sciences, Tehran, Iran. Abiri.m@iums.ac.ir.
15
Kawsar Human Genetics Research Center, 41 Majlesi St., Vali Asr St., Tehran, 1595645513, Iran. zeinali@kawsar.ir.
16
Department of Molecular Medicine, Biotech Research Center, Pasteur Institute of Iran, Tehran, Iran. zeinali@kawsar.ir.

Abstract

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.

KEYWORDS:

Consanguinity; Genetic counseling; Metabolism; Phenylketonuria

PMID:
30159852
DOI:
10.1007/s10545-018-0228-6

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