Balkan Journal of Medical Genetics最新文献

The CYP2C19*2 c.681G>A (rs4244285) loss-of-function (LOF) allele has been associated with reduced clopidogrel efficacy and increased risk of major adverse cardiovascular events (MACE). PGx-guided treatment, despite the recommendations, is not fully implemented in routine clinical practice. The primary aim of this hybrid retrospective-prospective study was to determine whether identifying CYP2C19 LOF patients may benefit the antiplatelet drug prescribing decisions made in Kosovo. The study cohort consisted of clopidogrel treated patients presenting at the University Clinical Center in the period from December 2023 to May 2024. To evaluate the correlation between CYP2C19 LOF and the treatment outcome in a follow-up period of 2 years, we first assessed the CYP2C19*2 genotype using the Taq Man Real Time PCR method. Among 150 patients, 58 (19.33%) were identified as carriers CYP2C19*2 LOF allele. The observed allele distribution was significantly different when compared with the one reported for a healthy Kosovar population (13.03%). CYP2C19*2 LOF carriers exhibited a 1.6-fold higher probability of developing cardiovascular disease compared to non-carriers, based on allelic and codominant model of statistical analysis (OR=1.60; 95% CI=1.08-2.37; p=0.018 and OR=1.64; 95% CI=1.04-2.57; p=0.031, respectively). The median observation time of follow up was not reached until this analysis was conducted. Our data supports the potential association of the CYP2C19*2 LOF allele with an increased risk for CVD in the population of Kosovo. Our data add to the evidence advising careful consideration of CYP2C19 genetic diversity when recommending PGx-guided clopidogrel therapy, particularly in populations, such the Kosovar, where genetic determinants are not yet fully elucidated.

The association between small for gestational age birth and chromosomal abnormalities identified through karyotyping is well-established. Notably, advancements in cytogenetic techniques have shifted from routine karyotyping to the recommended use of microarray technology. This transition allows higher resolution and the detection of sub-microscopic copy number variants (CNVs). Our study included 49 patients born small for gestational age, 27 males and 22 females. Clinical data were gathered from reports by clinical genetic specialists, and a questionnaire was included in the referral list to our laboratory. All participants were of pediatric age, ranging from neonatal to 12 years old. Chromosomal microarray testing was conducted by the Agilent SurePrint G3 Human CGH Microarray 8×60K. The application of molecular karyotyping yielded clinically significant results in 16 cases (32.65%), which included 13 deletions and 6 duplications. Three patients presented with two clinically significant CNVs (csCNVs). In ten cases, we identified recurrent microdeletion or microduplication syndromes well-documented in the literature: Williams syndrome as the most commonly identified (three patients), and others like Koolen de Vries, Prader-Willi, Miller-Dieker, Dryer, DiGeorge syndrome, 7q11.23 microduplication, 16p13.11 microdeletion, and 1q21.1 microdeletion syndrome. Six patients had rare non-recurrent pathological CNVs. There was no statistically significant difference between patients with csCNVs and those without regarding the presence of intellectual disabilities, central nervous system, cardiac or skeletal malformations. Chromosomal microarray proves to be a useful diagnostic tool in the etiology diagnosis of children born small for gestational age.

Cowden syndrome (CS) represents a rare autosomal dominant disorder caused by mutations in the PTEN gene located on chromosome 10q23.3. This entity belongs to the PTEN hamartoma tumor syndrome (PHTS) spectrum. The PTEN gene encodes a tumor suppressor protein crucial for regulating cell growth, survival, and apoptosis. Pathogenic mutations in PTEN result in dysregulated cell proliferation, manifesting clinically as benign and malignant growths across various tissues. CS is characterized by a predisposition to multiple hamartomas and an elevated risk of cancers, most notably in the skin, soft tissues, thyroid, breast, and gastrointestinal tract. In pediatric patients, macrocephaly is frequently the earliest feature, often accompanied by developmental delays and neurological deficits. This case series details the clinical evolution and multidisciplinary management of two siblings with CS and normal psychomotor development. Genetic testing identified a familial PTEN mutation, with multiple affected relatives, including the siblings' father, paternal aunt and paternal grandfather, each displaying distinct phenotype. This familial clustering highlights the autosomal dominant inheritance of CS and points out the critical importance of early genetic testing, vigilant surveillance, and tailored counselling for at-risk relatives. Phenotypic variability observed between members of the same family points out the difficulties in predicting transgenerational outcomes and complicates genetic counselling.

Background: Male infertility is a complex pathophysiological disorder. At least 2000 genes are implicated in the etiology of male infertility, making it a very complex genetic condition. In cases of male infertility, genetic testing using next-generation sequencing (NGS) technology may be useful for diagnosis. Thus, the purpose of this investigation was to apply the diagnostic offer for genetic variant identification using an NGS panel.

Methods: We developed an NGS gene panel that we used in 85 infertile male patients. The panel consisted of 132 genes exploring the genetic causes of male infertility; namely spermatogenesis failure due to single-gene mutations, central hypogonadism, androgen insensitivity syndrome, congenital hypopituitarism, and primary ciliary dyskinesia etc.

Results: A total of 85 patients (85 males) between 21 year and 45 years old were included in the study group. NGS analysis had been applied in all the primary infertility cases. As a result of NGS analysis, 58 clinical variants in 28 genes were detected in 41 patients (%48.23- 41/85).

Conclusion: Consequently, pre-diagnostic genes included in a custom-made NGS panel test can enhance genetic diagnostic testing and have an impact on the clinical management of male infertility.

Primary hyperparathyroidism (PHPT) is a common endocrine disorder characterized by the overactivity of the parathyroid glands. While a few genes have been linked to a predisposition for PHPT, the genetic foundation of the disease remains unclear, despite it being the third most prevalent endocrine disorder. This pilot study aimed to investigate, for the first time, the potential association between specific variants in Annexin A2 (ANXA2-rs7170178, rs17191344, rs11633032), Mediator Complex Subunit 12 (MED12-rs1057519912), Calmodulin 1 (CALM1-rs12885713), and Mitogen-Activated Protein Kinase 1 (MAPK1-rs1057519911) genes with PHPT. Previous expression analyses have indicated that the proteins related to these genes are involved in parathyroid adenomas or PTH signaling. Fifty unrelated PHPT patients and an equal number of healthy controls were enrolled in the study. Genotyping was conducted using the polymerase chain reaction - restriction fragment length polymorphism assay. Statistical analysis was performed to assess the connection between genetic variants and PHPT. Our results revealed no significant differences in genotypes' or alleles' distributions of any of the studied variants between PHPT patients and controls. These findings suggest that these variants may not be linked to PHPT in the studied population. This pilot study, focusing on a Caucasian group of PHPT patients, contributes to the existing genetic data for future meta-analyses, which will provide a more precise definition of the genetic factors associated with PHPT susceptibility worldwide.

Congenital diarrheal disorders (CDD) are a group of rare inherited intestinal disorders, among which CDD7 was recently identified to be associated with only 24 mutations in gene coding for diacylglycerol-acyltransferase 1 (DGAT1). We report on a female patient who presented with diarrhea, vomiting, hypoalbuminemia, and failure to thrive after birth. Two novel variants of c.1215_1216delAG and c.838C>T were found in the DGAT1 gene by whole exome sequencing, which was confirmed to be compound heterozygous by Sanger sequencing. Her symptoms and nutritional status improved significantly after 1 year of a fat-restricted enteral diet. Weight for age and weight for length increased from -5.0 SDS and -4.0 SDS at 3 months to +0.08 SDS and +1.75 SDS at 15 months, respectively. This report expanded the mutation spectrum of DGAT1-related CDD7 and enriched our knowledge of the clinical features. Moreover, early fat-restricted enteral diet intervention was suggested for the treatment of such patients.

The pathogenic variants in the telomerase reverse transcriptase (TERT) gene have been identified in adults with idiopathic pulmonary fibrosis, while their connection to childhood diffuse lung disease has not yet been described. Within this study, we present a case of a five-month-old, previously healthy infant, with early-onset respiratory failure. The clinical suspicion of diffuse lung disease triggered by cytomegalovirus (CMV) pneumonitis was based on clinical and radiological presentation. Multiorgan involvement was not confirmed. Considering the possible connection between CMV pneumonitis and early-onset respiratory failure, clinical exome sequencing was performed and a novel variant, classified as likely pathogenic in the TERT gene (c.280A>T, p.Lys94Ter) was detected. After segregation analysis yielded negative results, the de novo status of the variant was confirmed. Respiratory support, antiviral and anti-inflammatory therapy offered modest benefits, nevertheless, eighteen months after the initial presentation of disease, an unfavourable outcome occurred. In conclusion, severe viral pneumonia has the potential to induce extremely rare early-onset diffuse lung disease accompanied by chronic respiratory insufficiency. This is linked to pathogenic variants in the TERT gene. Our comprehensive presentation of the patient contributes to valuable insights into the intricate interplay of genetic factors, clinical presentations, and therapeutic outcomes in cases of early-onset respiratory failure.

In this study, we aimed to investigate the levels of Fibroblast Growth Factor-8 (FGF-8), FGF-10, FGF-Receptor-2 (FGFR-2), Androgen receptor (AR), Estrogen receptor alpha and beta (ER-α and ER-β) in the foreskins of children with and without hypospadias.

Methods: Samples from the foreskins of 20 children with hypospadias and 20 skin samples from children without hypospadias between the ages of 14 months and 12 years were taken during circumcision or hypospadias correction surgery for immunohistochemical (IHC) examination of these markers. In IHC examination, it was shown that ER-α, ER-β and AR receptors were more involved in the foreskin of children with hypospadias than in the fore-skin of without hypospadias children, and FGF-8, FGF-10 and FGFR-2 were lower (p<0.05). ER and AR uptake were higher in hypospadias tissue samples and FGF-8, FGF-10, and FGFR-2 uptakes were lower compared to without hypospadias children's tissue samples, and these factors were supported by affecting each other in the development of hypospadias. The limited number of studies on this subject in the literature and the contradictory results of the findings indicate that more research should be done on this subject in the future.

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. One of the best established CLL prognostic markers is the somatic hypermutational status of the IGHV gene which is a part of the immunoglobulin heavy chain variable region. Technology for IGHV genotyping has been optimized and has been applied in routine diagnostics for the first time in Bulgaria. A total of 105 patients with CLL from different Bulgarian regions were tested. IGHV mutational status was determined by Sanger sequencing on total genomic DNA (gDNA) or RNA extracted from mononuclear cells. All sequencing profiles were analyzed with the IMGT/V-QUEST tool. Within the course of the analysis a high percentage of IGHV unmutated status was established in the Varna district on the Black Sea (Northeast Bulgaria). In addition, the IGHV genotyping performed on gDNA revealed a rare case with multiple rearrangements. The present data from IGHV genotyping will help in choosing the proper treatment for the benefit of Bulgarian CLL patients.

The goal of the current study was to determine the high-resolution frequencies of the HLA-DRB1 alleles among the analyzed Romanian cohort of healthy stem cell donors. Using Next Generation Sequencing (NGS), we estimated class II HLA-DRB1 allele frequencies to a 6-digit resolution through HLA typing in a Romanian cohort of healthy individuals. The study for HLA genotyping included 420 willing donors from the National Registry of Voluntary Hematopoietic Stem Cell Donors (RNDVCSH). In 2020 and 2021, peripheral blood samples were collected and transported to the Fundeni Clinical Institute. We used the Immucor Mia Fora NGS MFlex kit for HLA genotyping. Forty-one different alleles were detected in 420 analyzed samples, out of which the most frequent HLA-DRB1 alleles were DRB1*16:01:01 (12.6%), DRB1*11:04:01 (12.1%) and DRB1*03:01:01 (12%). The HLA-DRB1*11:01:02 and -DRB1*08:04:01, -DRB1*05:01:01, -DRB1*13:05:01, -DRB1*14:07:01, -DRB1*09:01:02, -DRB1*11:02:01, -DRB1*04:07:01, -DRB1*15:03:01, -DRB1*03:02:01, -DRB1*04:06:02, -DRB1*04:08:01, -DRB1*14:05:01 were identified only once. The results revealed similarities with countries belonging to the Eastern Europe, the Balkans and the Caucasus regions. Further studies on larger Romanian cohorts are needed for confirming the current results.