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As the most common type of inherited retinal degenerative disease, retinitis pigmentosa (RP) has taken clinical and prenatal attention. Considering the clinical importance of consanguineous marriages, new mutations in this type of pregnancy have a high risk and increase the importance of Prenatal Diagnosis (PND). In vitro analysis was done through Whole Exome Sequencing (WES) for a 36-year-old woman who was referred to a genetic laboratory in Kermanshah in 2021 for PND. The woman had consanguineous marriage and was pregnant with twins (a boy and a girl). Mutation confirmation tests were also performed on her husband and both fetuses to find mutations. Moreover, in silico analyses were performed by SWISS-MODEL, ProSA, Molprobity, Swiss-Pdb Viewer, and ERRAT. The WES analysis showed a novel mutation of the RP2 gene (exon2:c. 359G>C: p.R120P) in the 36-year-old pregnant woman. Mutations identified in her husband and her twins revealed changes in protein conformations. Further modeling and validation evaluations showed the replacement of Arg by Pro at the 120th residue site of the cognate protein. For the first time, our report introduced a novel missense mutation in the RP2 gene associated with severe signs of RP in an Iranian family based on an X-linked recessive pattern of genetic inheritance. These findings may pave the way for a better diagnosis of RP in genetic counseling and PND. [ABSTRACT FROM AUTHOR]

Background: Citrullinemia type 1 is an autosomal recessive disease resulting in ammonia accumulation in the blood, and if uncontrolled may progress to coma or death in the early months after birth. Cases presentation: 7 families from Southwest Iran having one or more children in their families or relatives, who died in the early months after birth due to citrullinemia type 1 visited for genetic counseling and prenatal diagnosis. Whole-exome sequencing was performed on peripheral blood specimens and chorionic villus samples. Sanger sequencing confirmed the genetic results. Both parents were identified as carriers for the exon 15 c.1168G>A mutation in each family. The fetus in 6 out of 7 families was homozygote for A substitution on the argininosuccinate synthetase 1 gene. Conclusion: The presence of a common mutation in the argininosuccinate synthetase 1 gene in all affected families of Southwest Iran shows a possible population cluster in this area. [ABSTRACT FROM AUTHOR]

• Detecting genetic defects in a large number of SCID patients. • Molecular diagnosis is a critical step for genetic counseling, carrier detection, and prenatal diagnosis in SCID patients. • Applying rational ways based on immunological and clinical findings can be very effective in managing the disease and reducing costs. Severe combined immunodeficiency (SCID) is the most severe form of primary immunodeficiency disorders that is characterized by impaired early T lymphocyte differentiation and is variably associated with abnormal development of other lymphocyte lineages. SCID can be caused by mutations in more than 20 different genes. Molecular diagnosis in SCID patients contributes to genetic counseling, prenatal diagnosis, treatment modalities, and overall prognosis. In this cohort, the clinical, laboratory and genetic data related to Iranian SCID patients were comprehensively evaluated and efficiency of stepwise sequencing methods approach based on immunophenotype grouping was investigated Clinical and laboratory data from 242 patients with SCID phenotype were evaluated. Molecular genetic analysis methods including Sanger sequencing, targeted gene panel and whole exome sequencing were performed on 62 patients. Mortality rate was 78.9% in the cohort with a median follow-up of four months. The majority of the patients had a phenotype of T-NK-B+ (34.3%) and the most severe clinical manifestation and highest mortality rate were observed in T-NK-B- SCID cases. Genetic mutations were confirmed in 50 patients (80.6%), of which defects in recombination-activating genes (RAG1 and RAG2) were found in 16 patients (32.0%). The lowest level of CD4+ and CD8+ cells were observed in patients with ADA deficiency (p = 0.026) and IL2RG deficiency (p = 0.019), respectively. Current findings suggest that candidate gene approach based on patient's immunophenotype might accelerate molecular diagnosis of SCID patients. Candidate gene selection should be done according to the frequency of disease-causing genes in different populations. Targeted gene panel, WES and WGS methods can be used for the cases which are not diagnosed using this method. [ABSTRACT FROM AUTHOR]

Introduction: Hearing impairment is a complex medical disorder which has genetic and non-genetic causes. Gap Junction Protein Beta 2 (GJB2) gene variant is a well-known disease-causing gene among patients with hearing impairment. The frequencies of genetic variants in the GJB2 gene are different in each population. This study aimed to discuss the GJB2 gene status in an Iranian population with hearing impairment who referred for prenatal testing. Materials and Methods: This cross-sectional study was conducted in a genetic laboratory affiliated with Mashhad Jahad Daneshgahi, Mashhad, Iran. A total number of 21 bilateral hearing impaired patients were enrolled in this study. The exons for target GJB2 gene were amplified by polymerase chain reaction after the confirmation of the hearing impairment and the exclusion of the acquired causes of hearing loss. Results: The c.35delG and c.79G>A variants were the first and second most common variants in the study population, respectively. The mean age of the patients was 27.5 (8.7) years and 12 cases were male. There was no significant association between hearing impairment degree and age and heterozygosity status (P=0.376 and P=.074 respectively). Conclusion: The c.35delG and c.79G>A variants were determined as the first and second most common variants in the GJB2 gene, respectively. The mean age of 26 years in this study population indicates the late referral for the evaluation of the hearing difficulty. Furthermore, it highlights the further need to encourage families with a history of hearing impairment to engage in genetic counseling. [ABSTRACT FROM AUTHOR]

Congenital Fibrosis of the Extra Ocular Muscles1 (CFEOM1) is an autosomal dominant condition, caused by mutation in the KIF21A and TUBB3. It is characterized by congenital non-progressive restrictive ophthalmoplegia and ptosis. Mutational analysis of the known genes in such rare diseases by Sanger sequencing not only prevents wasting the time and expenses but also speeds diagnosis process, genetic counseling, and the possibility of prenatal diagnosis. Here, for the first time, association of pathogenic variant c.2860C>T in KIF21A gene in an Iranian family with positive history of CFEOM1A was reported. [ABSTRACT FROM AUTHOR]

Background: Cystic fibrosis (CF) is one of the most common autosomal recessive disorders in Caucasian population. The incidence of disorder varies among different religious, ethnic and geographical isolates. The aim of this study was to identify the spectrum and the frequency of known and unknown disease-causing mutations in Iranian CF patients. Methods: Genomic DNA was extracted from peripheral whole blood with a QIAamp DNA Mini-Kit. Mutation analysis was done in the CFTR gene including complete coding region and intron/exon boundaries using a direct sequencing method. Results: In general, ten mutations were identified in 27 CF cases. Two out of 10 mutations, 754delT and GGTGGCdel/TTGins, were reported as novel mutations. The most common observed mutations in patients were R334W (40.74%), ΔF508 (18.5%), K710X (12.96%) and D110H (5.5%), 1897C>G (1.85%), R1162X (1.85%), S466X (1.85%) and T1036I (1.85%). Conclusion: The finding indicated a unique mutation panel which can be used in genetic counseling, prenatal diagnosis and future screening of CF in Iran. Although ΔF508 is the most common mutation in other populations including Caucasian, this mutation seem not to have an important role in Iranian CF patients. Findings suggest that a different approach in molecular genetics diagnostic strategies in Middle Eastern countries including Iran should be considered. [ABSTRACT FROM AUTHOR]

Background: Thalassemic disorders are the most prevalent monogenic hereditary diseases around the world caused by decreased and altered synthesis or agenesis in one or more globin chains. Families who have a child with thalassemia major face a myriad of significant problems. Hormozgan province ranks second with thalassemic patients in Iran. Therefore, current research is aimed to analyze the reproductive behavior of such families in the southern province of Iran. Methods: In this descriptive study 190 mothers of patients suffering from thalassemia major were included. The reproductive behavior of mothers was investigated by a questionnaire regarding the number of thalassemic infants born after their first child with thalassemia major. Results: About 23% of these mothers had more than 1 child with major thalassemia. The findings showed that the reasons for conception among these mothers were to have a healthy child (64.2%) and to have a boy (20%). In about 92.6% of mothers CVS test was not performed. Conclusion: This study showed that awaring mothers and families regarding the prevention of birth of afflicted infants and provision of accessible diagnostic facilities can reduce the number of children with thalassemia major. [ABSTRACT FROM AUTHOR]

The major defect in α-thalassemia (α-thal) is a single or double gene deletion. The aim of this study was to evaluate the α-thal mutations in two provinces of Southern Iran, Fars & Kohkeloye and Bouyer Ahmad. A total of 2000 subjects with microcytic hypochromic anemia was selected as a study group; finally, 1177 subjects were found to be α-thal mutation carriers by gap-polymerase chain reaction (gap-PCR) protocols and were confirmed by multiplex PCR and reverse hybridization test strips. A total of 1195 mutated α-globin alleles was identified in these patients that includes at least 10 different gene mutations. The most common mutation found was -α3.7 (rightward deletion) (71.7%%) and α−5 nt (IVS-I, -TGAGG) and the polyadenylation signal site (poly A1; AATAA A>AATAA G) were the second and third most common mutations (7.0 and 4.2%%, respectively). In countries like Iran, with a high prevalence of thalassemia, identifying different mutations is helpful in carrier screening, genetic counseling and prenatal diagnosis of at-risk couples for the prevention of the birth of babies affected by severe thalassemic anomalies. [ABSTRACT FROM AUTHOR]

Abstract: In Iran, the prevalence of beta-thalassemia trait is approximately 4–8% in most areas, and in Mazandaran province 10% of the population are carriers. Twenty four beta-globin gene mutations were identified in 1635 persons with beta-thalassemia trait using reverse dot blot and restriction fragment length polymorphism analysis. The predominant mutations included IVSII-1 (G-A) (61%), codon 30 (G-C) (7.5%), codon 22 (−7bp) (6.2%), codon 8 (−AA) (5.4%) and IVSI-5 (G-C) (3.6%). These mutations were in different haplotypes, with IVSII-1 being the most heterogeneous. Other less frequent mutations included IVS-II-745 (C-G), codon 44 (−C), codon 39 (C-T), codon 5 (−CT), IVS I-110 (G-A), IVSI-130 (G-C), Fr8/9 (+G), IVSI-1 (G-A), and IVSI (−25bp). All rare mutations except IVSI-130 were encountered in a unique haplotype. The diversity of these mutations reflects the historical admixture of genes in the region. The high prevalence of IVSII-1 (G-A) compared to other parts of the country and the world suggests a founder effect. Our data provide a basis for genetic counseling and prenatal diagnosis. [Copyright &y& Elsevier]