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.
GJB2 mutation analysis is used routinely as a first step in genetic testing for autosomal recessive non-syndromic sensorineural hearing loss. Although most GJB2 mutations can be detected by sequencing of the exon 2 of this gene, a prevalent splice mutation, c.-23+1G>A (IVS1+1G>A), is not usually included in the analyzed region. In this study, we have developed an ARMS-PCR strategy for detection of this mutation among Iranian deaf individuals. A total of 418 Iranian individuals with hearing loss consistent with autosomal recessive non-syndromic sensorineural hearing loss based on audiological test result, medical history, physical examination and pedigree of the family, were included in this study. c.35delG and c.-23+1G>A mutations were detected by using ARMS-PCR. Direct sequencing of the exon 2 of the GJB2 gene was performed for mutation analysis of the coding region of this gene. Among 418 investigated cases, a total of 81 patients (~19.4 %) with biallelic pathogenic mutations in the GJB2 gene and 13 cases with only one pathogenic mutant allele were identified. The total allele frequencies of the two most frequent mutations, c.35delG and c.-23+1G>A, among mutated alleles were found to be around 59 and 15.7 %, respectively. High frequency of the c.35delG and c.-23+1G>A mutations among Iranian deaf individuals shows the importance of developing rapid and cost-effective methods for primary mutation screening methods before performing direct sequencing.
Background: Hemophilia A (HA) is an X-linked recessive bleeding disorder with a high rate of genetic heterogeneity. The present study was conducted on a large cohort of Iranian HA patients and data obtained from databases. Methods: A total of 622 Iranian HA patients from 329 unrelated families who had been referred to a medical genetics laboratory in Tehran from 2005 to 2019, were enrolled in this retrospective, observational study. Genetic screening of pathogenic variants of the F8 gene was performed using inverse shifting PCR, direct sequencing, and multiplex ligation-dependent amplification (MLPA). Point mutation frequencies in different exons were analyzed for our samples as well as 6031 HA patients whose data were recorded in a database. Results: A total of 144 different pathogenic or likely pathogenic variants including 29 novel variants were identified. A strategy to decrease costs of genetic testing of HA was suggested based on this finding. Conclusion: This study provides comprehensive information on F8 pathogenic/likely pathogenic variants in Iranian HA patients which improves the spectrum of causative mutations and can be helpful to clinicians and medical geneticists in counseling and molecular diagnosis of HA.
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