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Background: Congenital cataract (CC) is the most common reason for visual loss and blindness at birth or early childhood worldwide. The autosomal dominant (AD) inheritance is reported as the most frequent transmission pattern for CC. Connexin 46 (Cx46 coded by GJA3 gene) belongs to the gap junction proteins family which has the main function in the cell communication system of the eye lens. Methods: In the present research, whole-exome sequencing (WES) was done for proband diagnosed by CC, and Co-segregation analysis using Sanger sequencing was performed for the candidate variant on healthy and affected family members. The candidate variant was analyzed with appropriate bioinformatics software and then classified according to the ACMG guideline. Results: WES analysis of proband recognized a novel heterozygous c.146 A>C (p.Q49P) variant in the exon 2 of the GJA3 gene leading to the substitution of a highly conserved Glutamine by Proline at codon 49. The linkage of CC with this variant was observed for three generations in a proband family with AD inheritance. This variant is located on phylogenetically conserved extracellular loop E1 of protein. Extracellular loops play the main role to mediate hemichannel docking between connexons and regulating voltage gating of the channel. Conclusion: Our finding emphasized the role of Cx46 in the pathogenesis of ADCC and the extended mutation spectrum of the GJA3 gene in association with CC.

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.

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.

Background Dysferlinopathies are a group of autosomal recessive limb‐girdle muscular dystrophies (LGMDs) caused by mutations in DYSF (#603,009). This gene encodes a transmembrane protein called dysferlin. Since there are few reports on Iranian dysferlinopathy patients, we tried to identify the DYSF mutations in affected individuals of Iran. Methods Eight unrelated Iranian families have been selected for this study. Sanger sequencing followed by haplotype analysis was performed to identify individual variations in DYSF sequence. Identified variants were analyzed, and their pathogenicity was interpreted according to the recommendations of the American College of Medical Genetics and Genomics. Results We identified two new mutations in DYSF, the first one is a nonsense mutation c.2419C > T (p.Gln807*), which eliminates downstream part of the protein. Another novel mutation is c. (1,053 + 1_1,054‐1)_(1,397 + 1_1,398‐1)del, which causes deletion of the DNA segment from exon 12 to exon 15. Conclusion Two of the other six families are from the same ethnicity and share the same mutation and haplotype patterns, suggesting a founder mutation. Genetic analysis of dysferlinopathy can prevent a wrong diagnosis of myositis for these patients., Dysferlinopathies are a group of autosomal recessive limb‐girdle muscular dystrophies which can be observed in countries with high consanguineous rate like Iran. Sanger sequencing followed by haplotype analysis was performed to identify individual variations in DYSF sequence which provided some recurrent and novel mutation in Iranian population. We also identified two unrelated families with same haplotype and mutation which is suggestive of founder effect.

Isolated Methylmalonic acidemia/aciduria (MMA) is a group of inborn errors of metabolism disease which is caused by defect in methylmalonyl-CoA mutase (MCM) enzyme. The enzyme has a key function in the catabolism of branched chain amino acids (BCAA, isoleucine, and valine), methionine, and threonine. MCM is encoded by a single gene named “MUT”. Other subtypes of MMA are caused by mutations in cblA (encoded by MMAA) and cblB (encoded by MMAB), which is involved in the synthesis of methylmalonyl–coenzyme A cofactor. Different types of mutations have been identified as the cause of MMA. However, the mutation spectrum of MMA in Iran has not been studied so far. Here, we aimed to investigate the MMA causative mutations in the Iranian population. Using STR (Short Tandem Repeat) markers, we performed autozygosity mapping to identify the potential pathogenic variants in 11 patients with clinical diagnosis of MMA. Nineteen STR markers which are linked to the MUT, MMAA and MMAB genes (the genes with known causative mutations in MMA) were selected for PCR-amplification using two recently designed multiplex PCR panels. Next, the families that were diagnosed with homozygous haplotypes for the candidate genes were directly sequenced. Five novel mutations (c.805delG, c.693delC, c.223A > T, c.668A > G and c.976A > G in MUT) were identified beside other 4 recurrent mutations (c.361insT in MUT, c.571C > T and c.197–1 G > T in MMAB and c.1075C > T in MMAA). In silico analyses were also performed to predict the pathogenicity of the identified variants. The mutation c.571C > T in MMAB was the most common mutation in our study.