Molecular study of PKD1 & PKD2 genes by linkage analysis and determining the genotype/phenotype correlations in several Iranian families with autosomal dominant polycystic kidney disease

Background: Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder with genetic heterogeneity. Up to three loci are involved in this disease, PKD1 on chromosome 16p 13.3, PKD2 on 4q21, and a third locus of unknown location. Methods: Here we report the first molecular genetic study of ADPKD and the existence of locus heterogeneity for ADPKD in the Iranian population by performing linkage analysis on 15 affected families. Results: Eleven families showed linkage to PKD1 and two families showed linkage to PKD2. In two families, PKD1 markers are common in all affected members but PKD2 markers were not informative. Conclusion: The results of this study demonstrate significant locus heterogeneity in autosomal dominant PKD in Iran. Analysis of clinical data confirms a milder ADPKD phenotype for PKD2 families. Our results showed relatively high heterozygosity rates and PIC values for some markers, while the most informative markers were KG8 and 16AC2.5 for PKD1 gene and AFM224x6 for PKD2 gene

Developing a Questionnaire for Iranian Women's Attitude on Medical Ethics in Vaginal Childbirth

Background: Vaginal delivery is one of the challenging issues in medical ethics. It is important to use an appropriate instrument to assess medical ethics attitudes in normal delivery, but the lack of tool for this purpose is clear. Objectives: The aim of this study was to develop and validate a questionnaire for the assessment of women’s attitude on medical ethics application in normal vaginal delivery. Patients and Methods: This methodological study was carried out in Iran in 2013 - 2014. Medical ethics attitude in vaginal delivery questionnaire (MEAVDQ) was developed using the findings of a qualitative data obtained from a grounded theory research conducted on 20 women who had vaginal childbirth, in the first phase. Then, the validation criteria of this tool were tested by content and face validity in the second phase. Exploratory factor analysis was used for construct validity and reliability was also tested by Cronbach’s alpha coefficient in the third phase of this study. SPSS version 13 was used in this study. The sample size for construct validity was 250 females who had normal vaginal childbirth. Results: In the first phase of this study (tool development), by the use of four obtained categories and nine subcategories from grounded theory and literature review, three parts (98-items) of this tool were obtained (A, B and J). Part A explained the first principle of medical ethics, part B pointed to the second and third principles of medical ethics, and part J explained the fourth principle of medical ethics. After evaluating and confirming its face and content validity, 75 items remained in the questionnaire. In construct validity, by the employment of exploratory factor analysis, in parts A, B and J, 3, 7 and 3 factors were formed, respectively; and 62.8%, 64% and 51% of the total variances were explained by the obtained factors in parts A, B and J, respectively. The names of these factors in the three parts were achieved by consideration of the loading factor and medical ethics principles. The subscales of MEAVDQ showed significant reliability. In parts A, B and J, Cronbach’s alpha coefficients were 0.76, 0.72 and 0.68, respectively and for the total questionnaire, it was 0.72. The results of the test–retest were satisfactory for all the items (ICC = 0.60 - 0.95). Conclusions: The present study showed that the 59-item MEAVDQ was a valid and reliable questionnaire for the assessment of women’s attitudes toward medical ethics application in vaginal childbirth. This tool might assist specialists in making a judgment and plan appropriate for women in vaginal delivery management

Whole genome sequencing identifies a duplicated region encompassing Xq13.2q13.3 in a large Iranian family with intellectual disability

Background The X chromosome has historically been one of the most thoroughly investigated chromosomes regarding intellectual disability (ID), whose etiology is attributed to many factors including copy number variations (CNVs). Duplications of the long arm of the X chromosome have been reported in patients with ID, short stature, facial anomalies, and in many cases hypoplastic genitalia and/or behavioral abnormalities. Methods Here, we report on a large Iranian family with X‐linked ID caused by a duplication on the X chromosome identified by whole genome sequencing in combination with linkage analysis. Results Seven affected males in different branches of the family presented with ID, short stature, seizures, facial anomalies, behavioral abnormalities (aggressiveness, self‐injury, anxiety, impaired social interactions, and shyness), speech impairment, and micropenis. The duplication of the region Xq13.2q13.3, which is ~1.8 Mb in size, includes seven protein‐coding OMIM genes. Three of these genes, namely SLC16A2, RLIM, and NEXMIF, if impaired, can lead to syndromes presenting with ID. Of note, this duplicated region was located within a linkage interval with a LOD score >3. Conclusion Our report indicates that CNVs should be considered in multi‐affected families where no candidate gene defect has been identified in sequencing data analysis

Comprehensive genotype‐phenotype correlation in AP‐4 deficiency syndrome; Adding data from a large cohort of Iranian patients

Mutations in adaptor protein complex‐4 (AP‐4) genes have first been identified in 2009, causing a phenotype termed as AP‐4 deficiency syndrome. Since then several patients with overlapping phenotypes, comprised of intellectual disability (ID) and spastic tetraplegia have been reported. To delineate the genotype‐phenotype correlation of the AP‐4 deficiency syndrome, we add the data from 30 affected individuals from 12 out of 640 Iranian families with ID in whom we detected disease‐causing variants in AP‐4 complex subunits, using next‐generation sequencing. Furthermore, by comparing genotype‐phenotype findings of those affected individuals with previously reported patients, we further refine the genotype‐phenotype correlation in this syndrome. The most frequent reported clinical findings in the 101 cases consist of ID and/or global developmental delay (97%), speech disorders (92.1%), inability to walk (90.1%), spasticity (77.2%), and microcephaly (75.2%). Spastic tetraplegia has been reported in 72.3% of the investigated patients. The major brain imaging findings are abnormal corpus callosum morphology (63.4%) followed by ventriculomegaly (44.5%). Our result might suggest the AP‐4 deficiency syndrome as a major differential diagnostic for unknown hereditary neurodegenerative disorders

The recurrent missense mutation p.(Arg367Trp) in YARS1 causes a distinct neurodevelopmental phenotype

Abstract: Pathogenic variants in aminoacyl-tRNA synthetases (ARS1) cause a diverse spectrum of autosomal recessive disorders. Tyrosyl tRNA synthetase (TyrRS) is encoded by YARS1 (cytosolic, OMIM*603,623) and is responsible of coupling tyrosine to its specific tRNA. Next to the enzymatic domain, TyrRS has two additional functional domains (N-Terminal TyrRSMini and C-terminal EMAP-II-like domain) which confer cytokine-like functions. Mutations in YARS1 have been associated with autosomal-dominant Charcot-Marie-Tooth (CMT) neuropathy type C and a heterogenous group of autosomal recessive, multisystem diseases. We identified 12 individuals from 6 families with the recurrent homozygous missense variant c.1099C > T;p.(Arg367Trp) (NM_003680.3) in YARS1. This variant causes a multisystem disorder with developmental delay, microcephaly, failure to thrive, short stature, muscular hypotonia, ataxia, brain anomalies, microcytic anemia, hepatomegaly, and hypothyroidism. In silico analyses show that the p.(Arg367Trp) does not affect the catalytic domain responsible of enzymatic coupling, but destabilizes the cytokine-like C-terminal domain. The phenotype associated with p.(Arg367Trp) is distinct from the other biallelic pathogenic variants that reside in different functional domains of TyrRS which all show some common, but also divergent clinical signs [(e.g., p.(Phe269Ser)—retinal anomalies, p.(Pro213Leu)/p.(Gly525Arg)—mild ID, p.(Pro167Thr)—high fatality)]. The diverse clinical spectrum of ARS1-associated disorders is related to mutations affecting the various non-canonical domains of ARS1, and impaired protein translation is likely not the exclusive disease-causing mechanism of YARS1- and ARS1-associated neurodevelopmental disorders. Key messages: The missense variant p.(Arg367Trp) in YARS1 causes a distinct multisystem disorder.p.(Arg367Trp) affects a non-canonical domain with cytokine-like functions.Phenotypic heterogeneity associates with the different affected YARS1 domains.Impaired protein translation is likely not the exclusive mechanism of ARS1-associated disorders

Mutation analysis of BRCA1 and BRCA2 genes in Iranian high risk breast cancer families

Background: Telomerase is a ribonucleoprotein enzyme that synthesises telomeres after cell division and maintains chromosomal stability leading to cellular immortalization. Telomerase has been associated with negative prognostic indicators in some studies. The present study aims to detect any association between telomerase sub-units: hTERT and hTR and the prognostic indicators including tumour's size and grade, nodal status and patient's age. Methods: Tumour samples from 46 patients with primary invasive breast cancer and 3 patients with benign tumours were collected. RT-PCR analysis was used for the detection of hTR, hTERT, and PGM1 (as a housekeeping) genes expression. Results: The expression of hTR and hTERT was found in 31(67.4%) and 38 (82.6%) samples respectively. We observed a significant association between hTR gene expression and younger age at diagnosis (p = 0.019) when comparing patients ≤ 40 years with those who are older than 40 years. None of the benign tumours expressed hTR gene. However, the expression of hTERT gene was revealed in 2 samples. No significant association between hTR and hTERT expression and tumour's grade, stage and nodal status was seen. Conclusion: The expression of hTR and hTERT seems to be independent of tumour's stage. hTR expression probably plays a greater role in mammary tumourogenesis in younger women (≤ 40 years) and this may have therapeutic implications in the context of hTR targeting strategies

Hemoglobin Q-Iran detected in family members from Northern Iran: a case report

<p>Abstract</p> <p>Introduction</p> <p>Hemoglobin Q-Iran (α75Asp→His) is an important member of the hemoglobin Q family, molecularly characterized by the replacement of aspartic acid by histidine. The first report of hemoglobin Q-Iran and the nomenclature of this hemoglobinopathy dates back to 1970. Iran is known as a country with a high prevalence of α- and β-thalassemia and different types of hemoglobinopathy. Many of these variants are yet to be identified as the practice of molecular laboratory techniques is limited in this part of the world. Applying such molecular methods, we report the first hemoglobin Q-Iran cases in Northern Iran.</p> <p>Case presentation</p> <p>An unusual band was detected in an isoelectric focusing test and cellulose acetate electrophoresis of a sample from a 22-year-old Iranian man from Mazandaran Province. Capillary zone electrophoresis analysis identified this band as hemoglobin Q. A similar band was also detected in his mother's electrophoresis (38 years, Iranian ethnicity). The cases underwent molecular investigation and the presence of a hemoglobin Q-Iran mutation was confirmed by the amplification refractory mutation system polymerase chain reaction method. Direct conventional sequencing revealed a single guanine to cytosine missense mutation (c.226G > C; <it>G</it>AC ><it>C</it>AC) at codon 75 in the α-globin gene in both cases.</p> <p>Conclusion</p> <p>The wide spectrum and high frequency of nondeletional α-globin mutations in Mazandaran Province is remarkable and seem to differ considerably from what has been found in Mediterranean populations. This short communication reports the first cases of patients with hemoglobin Q found in that region.</p

Ethnic-specific distribution of mutations in 716 patients with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) occurs worldwide. The most common mutations in the CYP21A2 gene in 716 unrelated patients were analyzed and the mutations were grouped by ethnicity, as defined through self-declaration corroborated by review of pedigrees extending to two or three generations. Prevalent allelic mutations and genotypes were found to vary significantly among ethnic groups, and the predominance of the prevalent mutations and genotypes in several of these populations was significant. There are ethnic-specific mutations in the CYP21A2 gene. A large deletion is prevalent in the Anglo-Saxons; a V281L (1685 G to T) mutation is prevalent in Ashkenazi Jews; an R356W (2109 G to A) mutation is prevalent in the Croatians; an IVS2 AS -13 (A/C to G) mutation is prevalent in the Iranians and Yupik-speaking Eskimos of Western Alaska; and a Q318X (1994 C to T) mutation is prevalent in East Indians. Genotype/phenotype non-correlation was seen when at least one IVS2 AS -13 (A/C to G) mutation in the CYP21A2 gene was present. © 2007 Elsevier Inc. All rights reserved