A Comprehensive Overview of NF1 Mutations in Iranian Patients.

Neurofibromatosis type 1 (NF1) is a genetic disorder caused by mutations in the NF1 gene. This disorder shows nearly complete penetrance and high phenotypic variability. We used the whole-exome sequencing technique to identify mutations in 32 NF1 cases from 22 Iranian families. A total of 31 variants, including 30 point mutations and one large deletion, were detected. In eight cases, variants were inherited, while they were sporadic in the remaining. Seven novel variants, including c.5576 T > G, c.6658_6659insC, c.2322dupT, c.92_93insAA, c.4360C > T, c.3814C > T, and c.4565_4566delinsC, were identified. The current study is the largest in terms of the sample size of Iranian NF1 cases with identified mutations. The results can broaden the spectrum of NF1 mutations and facilitate the process of genetic counseling in the affected families.

Extreme ßHCG levels in first trimester screening are risk factors for adverse maternal and fetal outcomes.

Multiples of the normal median (MoM) of free ßHCG is a valuable parameter in evaluation of risk of adverse pregnancy outcomes. In the current retrospective study, we assessed the maternal and fetal outcomes in pregnant women having free ßHCG MoM levels < 0.2 or > 5 in their first trimester screening (FTS). Relative risk of trisomy 21 was significantly higher in patients having free ßHCG MoM > 5. On the other hand, relative risk of trisomies 13 and 18 and Turner syndrome were higher in those having free ßHCG MoM < 0.2. Other chromosomal abnormalities were nearly equally detected between those having free ßHCG MoM < 0.2 or > 5. Relative risk of hydrocephaly and hydrops fetalis was higher when free ßHCG MoM was below 0.2. On the other hand, relative risk of low birth weight was higher when free ßHCG MoM was above 5. Moreover, frequency of gestational diabetes mellitus, preeclampsia, preterm delivery and vaginal bleeding increased with levels of free ßHCG MoM. However, polyhydramnios had the opposite trend. Frequencies of premature rupture of membranes and pregnancy induced hypertension were highest among pregnant women having levels of free ßHCG MoM < 0.2. The current study indicates importance of free ßHCG MoM in identification of at-risk pregnancies in terms of both fetal and maternal outcomes. In fact, ßHCG MoM < 0.2 or > 5 can be regarded as risk factors for adverse maternal or fetal outcomes irrespective of the presence of other abnormalities in the FTS results.

Clinical and Molecular Findings of Autosomal Recessive Spastic Ataxia of Charlevoix Saguenay: an Iranian Case Series Expanding the Genetic and Neuroimaging Spectra.

Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS) is now increasingly identified from all countries over the world, possibly rendering it one of the most common autosomal recessive ataxias. Here, we selected patients harboring SACS variants, the causative gene for ARSACS, in a large cohort of 137 patients with early-onset ataxia recruited from May 2019 to May 2021 and were referred to the ataxia clinic. Genetic studies were performed for 111 out of 137 patients (81%) which led to a diagnostic rate of 72.9% (81 out of 111 cases). Ten patients with the molecular diagnosis of ARSACS were identified. We investigated the phenotypic and imaging spectra of all confirmed patients with ARSACS. We also estimated the frequency of ARSACS in this cohort and described their clinical and genetic findings including seven novel variants as well as novel neuroimaging findings. While the classic clinical triad of ARSACS is progressive cerebellar ataxia, spasticity, and sensorimotor polyneuropathy, it is not a constant feature in all patients. Sensorimotor axonal-demyelinating neuropathy was detected in all of our patients, but spasticity and extensor plantar reflex were absent in 50% (5/10). In all patients, brain magnetic resonance imaging (MRI) showed symmetric linear hypointensities in the pons (pontine stripes) and anterior superior cerebellar atrophy as well as a hyperintense rim around the thalami (thalamic rim). Although infratentorial arachnoid cyst has been reported in ARSACS earlier, we report anterior temporal arachnoid cyst in two patients for the first time, indicating that arachnoid cyst may be an associated imaging feature of ARSACS. We also extended molecular spectrum of ARSACS by presenting 8 pathogenic and one variant of unknown significance (VUS) sequence variants, which 7 of them have not been reported previously. MetaDome server confirmed that the identified VUS variant was in the intolerant regions of sacsin protein encoded by SACS.

A novel pathogenic variant of BRAT1 gene causes rigidity and multifocal seizure syndrome, lethal neonatal.

INTRODUCTION: Lethal neonatal rigidity and multifocal seizure syndrome (RMFSL) is a severe autosomal recessive epileptic encephalopathy characterized by microcephaly, rigidity, intractable focal seizures, apnea, and bradycardia at or soon after birth. RMFSL is related to BRCA1-associated ATM activator 1 (BRAT1) gene mutations. METHODS: An Iranian couple with history of infant death due to RMFSL was referred to our genetics lab for specialized genetic counseling and testing. Whole Exome Sequencing (WES) was applied. Following WES, Sanger sequencing was performed to confirm the candidate variant. RESULT: A novel nonsense variant (c.2041G > T, p. E681X) was identified in exon 14 of the BRAT1 gene. Based on the American College of Medical Genetics and Genomics guideline this variant was classified as a pathogenic variant. CONCLUSION: This research expands the spectrum of BRAT1 pathogenic variants in RMFSL syndrome and demonstrates the utility of WES in genetic diagnostic.

Fine-tuning of routine combined first- trimester screening: The ratio of serum-free- beta-human chorionic gonadotropin (fß-hCG) to pregnancy-associated plasma protein-A (PAPP-A) could improve performance of Down syndrome screening program, a retrospective cohort study in Iran.

OBJECTIVES: To evaluate the performance of the current national screening policy for Down syndrome (DS) in Iran and suggest a more efficient protocol with a wealth of a large series of first-trimester screening (FTS) data obtained from Nilou medical laboratory. To fulfill this aim, detection rate (DR), positive screening rate (PSR), false negative rate (FNR) and odds of being affected given a positive results (OAPR) were calculated at different cutoff risk. In the latest update of DS screening program in Iran, there is no place for intermediate group to be further investigated. Next, we proposed a novel parameter namely the ratio of fß-hCG multiple of the median (MoM) value to PAPP-A MoM value to delicately categorize FTS results in a way that reduce FNR without imposing unnecessary anxious and extra money on most families. METHODS: The present investigation was conducted retrospectively on 197,210 pregnancies undergoing FTS for aneuploidies in Nilou medical laboratory, Tehran, Iran, from March 2015 to February 2016. RESULTS: Intermediate risk group is important as 23 out of 45 FN fell in the range 1:250 to 1:1100. By applying the proposed index, the ratio of fß-hCG MoM to PAPP-A MoM and subsequent decision about NIPT, 8 out of 23 FN cases in intermediate group could be detected. CONCLUSION: Compared with the current policy, our novel proposed approach had better performance and could be applied by the Iran National Health Service to improve the screening program guideline.

Personalized evolutionary hypothesis in genomics and auxiliary lymph node through diverse subtelomeric signal profile.

Few available data on the genomic-somatic evolution in breast cancer create limitation to provide the appropriate clinical managements. As an example, human subtelomeres (ST) are diverse-prone and variable targets. STs, as hot spots, have positive and negative impacts on the status of health and malady. We showed higher subtelomere signal copy number (SCN) of specific chromosomes in genomics than in auxiliary lymph node (ALN). Dissimilarity of signal intensity (SI) is found for all chromosomes. Significantly higher SI in genomics than in ALN cells were specified as chromosomes 5, 6, 9-12, 16-19 for weak; 1, 5-9, 19, X for medium; and 2, 5, 9, 10, 16, 18 for strong SI. For lacking, and presence of one and two SCNs; p/q ratio reflected differences for all chromosomes; but, 2, 3, 5, 7, 8, 10, 16, 18, 20, and X chromosomes were involved for three SCN. Chromosomes 1, 4, 9, 12, 17-19 lacked three SCN in ALN and lymphocytes. Weak SI ratio was higher in p- than in q-arm in majority of chromosomes. Manner of evolution and diversity in p- and q-arms is expressive of a novel definition as two diverse domains with a personalized insight. These data have been accompanied by periodic charts as ST array profiles which provide specific and individualized pattern in breast neoplasm. Such profiling at genomics level could be considered as a prediction through the patients' life. Moreover, subtelomere territory by interacting with protein expression of Ki67, cyclin D1, and cyclin E; and molecular targets including telomere length at genomics and somatic level provides package of information to bridge cancer cell biology to the cancer clinic as "puzzling paradigm."

Expression analysis of MiR-21, MiR-205, and MiR-342 in breast cancer in Iran.

MicroRNAs (miRNAs) are short non-coding RNA molecules characterized by their regulatory roles in cancer and gene expression. We analyzed the expression of miR-21, miR-205, and miR-342 in 59 patients with breast cancer. Samples were divided into three different groups according to their immunohistochemistry (IHC) classification: ER-positive and/or PR-positive group (ER+ and/or PR+; group I); HER2-positive group (HER2+; group II); and ER/PR/HER2- negative (ER-/PR-/HER2-; group III) as the triple negative group. The expression levels of the 3 miRNAs were analyzed in the tumor samples and the compared with the normal neighboring dissected tumor (NNDT) samples in all three groups. The expression of miR-21 was similar in all three groups. In patients positive for P53 by IHC, positive for axillary lymph node metastasis and higher tumor stages, it appeared to have significantly elevated. However, significant increase was not found among the 18 fibroadenoma samples. Both miR-205 and miR-342 expressions were significantly down regulated in group III. We conclude that miR-21 does not discriminate between different breast cancer groups. In contrast, miR-205 and miR-342 may be used as potential biomarkers for diagnosis of triple negative breast cancer.

Expression of Testis Specific Genes TSGA10, TEX101 and ODF3 in Breast Cancer.

BACKGROUND: Breast cancer is the most common malignancy in women around the world so finding new biomarkers for early detection and also study on molecular aspects of breast cancer is valuable. Cancer testis genes are a group of genes expressed solely in testis and in a range of human malignancies. OBJECTIVES: In this study we determined the expression of cancer testis genes Tsga10, TEX101 and ODF3 in patients with breast cancer. MATERIALS AND METHODS: Fifty patients with breast cancer were enrolled in this study. Breast cancer cell lines MCF-7 and MDA-MB-231 were also used to determine the expression of testis cancer genes. For both patients and cell lines, cancer testis genes of TSGA10, TEX101 and ODF3 were determined by RT-PCR. The presence of auto antibody against these genes in patients' serums was carried on by ELISA method. RESULTS: Seventy percent of patients showed TSGA10 expression but none of them showed expression of TEX101 and ODF3. Fourteen percent of patients were positive for anti TSGA10 but all patients were negative for anti TEX101 and anti ODF3. Both of breast cancer cell lines exhibited very strong expression of TSGA10. CONCLUSIONS: Because of the important roles of Tsga10 in cell proliferation, we concluded that this gene may have a role in proliferation and survival of breast cancer cells and could be used for diagnosis and immunotherapy of breast cancer.