Balkan Journal of Medical Genetics最新文献

Congenital malformations can be found in all organ systems of a newborn. Almost two-thirds of congenital malformations have an unknown cause. There are minor (mM) and major (MM) congenital malformations. Searching for minor malformations has its vital place in everyday neonatology practice. Minor malformations are defined as physical variants that have no medical consequences and are mostly located on the face and distal parts of the extremities and are easily noticed. Minor malformations occur in approximately 15% of newborns. Minor congenital malformations are of great importance because they can be an indicator of the existence of major congenital malformations and syndromes. In a one-year retrospective study that analyzed the occurrence of 38 minor malformations through the year 2023 at the University Clinical Hospital of Mostar, there was an incidence of 10.59% of minor malformations. The most frequently recorded minor malformation was deep a sacral dimple at 44.72%, then poorly modeled ears at 15.08%, and moderate rectal diastasis at 14.58%. Three or more minor congenital malformations indicate one or more major congenital malformations. Major congenital malformations are severe structural defects of tissues and organs that endanger life, create serious functional disturbances and hinder the development of the child. In our country, there is currently a recorded incidence of 8.04%. The search for minor malformations in the newborn period is of great importance to children and the whole family, and the search must not be neglected.

Haemoglobin (Hb) Malay is variant haemoglobin with a β⁺⁺ thalassemia phenotype. The prevalence of Hb Malay in the Malaysian population was 5.5%. We describe a 58-year-old male who presented with symptomatic anaemia to the Hospital Universiti Sains Malaysia. Further history revealed that the patient had anaemia since the age of 28, and on regular follow-up at other hospital. Physical examination revealed pallor, jaundice and hepatosplenomegaly. The full blood count and peripheral blood smear showed hypochromic microcytic anaemia with anisopoikilocytosis, and many target cells. High-performance liquid chromatography results showed a β thalassemia trait. However, the diagnosis does not alight with the patient's condition. Bone marrow aspirate was completed and showed reactive changes and erythroid hyperplasia. A molecular test was then performed for β globin gene mutation detection using Multiplex Amplification Refractory Mutation System (M-ARMS) PCR method. This revealed the result as homozygous codon 19 mutation or Hb Malay. Therefore, in this case report we would like to highlight the laboratory approaches, the challenges faced by the usual haematological investigations and the importance role of molecular testing in the diagnosis of severe anaemia.

Early pregnancy loss (EPL) is the most common pregnancy complication, found in approximately 15% of all clinically recognized pregnancy complications. Up to date, various maternal as well as fetal factors are reported as a cause of EPLs. However, in approximately 50% of EPL cases, the exact cause is not clearly identified and these cases are referred as idiopathic. The aim of our study was to examine the association of four distinct variants in the ANXA5 gene and two variants within the VEGFA gene in a cohort of women with EPLs from North Macedonia. This group was compared to a control group of women matched by ethnic background without pregnancy loss and at least one live birth. We also aimed to establish an effective and cost-efficient method for their detection based on multiplex single-base extension. Among 190 women experiencing EPLs, and 190 samples from women without a history of pregnancy loss (control group), our results demonstrated a statistically significant prevalence of heterozygotes for the M2/ANXA5 haplotype in women with EPLs, compared to the control group (p=0.0006). In the analyses comparing genotypic frequencies for the variants in the VEGFA gene, higher frequencies were generally observed among women experiencing EPLs, however without statistical significance. Our study aligns with multiple studies showing that M2 and M1 ANXA5 haplotypes are more prevalent in patients with pregnancy loss and presents an affordable genotyping technique for the specific ANXA5 and VEGFA variants.

Background: Severe acute respiratory syndrome coronavirus-2 infection has spread uncontrollably worldwide. Among the most vulnerable groups in society are populations with multiple comorbidities, including individuals with Down syndrome (DS).

Aim: Our aim was to conduct an online survey to assess the impact of COVID-19 on DS individuals in Croatia. We also explored the views of their parents and caregivers about the challenges they faced during COVID-19.

Methods: The anonymous online survey was launched in March 2022 and remained open until October 2022. Participants were conducted online through closed group on Facebook. The survey included questions about participant characteristics, medical information, clinical presentation of COVID-19, and challenges faced by the parents during COVID-19.

Results: A total of 268 surveys were collected and analysed. We found that age and body mass index of DS individuals were significantly and positively correlated with the clinical presentation of COVID-19. Lack of social activities, cancelled therapies, and psychological problems were the most frequently cited challenges during the pandemic.

Conclusion: Clinicians and caregivers should primarily be alert to the same COVID-19 signs and symptoms that occur in the general population (fever, cough, shortness of breath). Ongoing therapies, social activities, and psychological support should be cited as indispensable for maintaining physical health and emotional well-being in DS individuals.

Background: Cystic fibrosis (CF) is a genetic disease characterized by a wide spectrum of severity, resulting from the inheritance of a mutant allele of the gene for cystic fibrosis transmembrane conductance regulator (CFTR). The aim of the study was to present a CFTR mutation analysis among the Albanian population and to identify rare variants.

Methods: We identified CFTR mutations in a representative cohort of CF patients comprising of Albanian patients and some Kosovo patients followed up by the Department of Pediatrics at the University Hospital Center "Mother Theresa" (UHCMT). Compiled clinical and genotypic data include 133 previously analyzed patients, of whom 116 have two identified mutations, 6 have only one known mutation, and 11 are unexamined.

Results: The most frequent mutation is F508del (83.19%), followed by 621+1G>T (2.45%). Other mutations identified in decrease order are E822X, G85E, G542X, R1066C, R1070Q, R1158X, G1349D, N1303K, S466X, 1811+1G->C, E831X, CFTRdele2,3(21kb).

Conclusions: The data suggest that most of these patients can benefit from new modulatory therapies targeting CFTR mutations, translating to very hopeful prospects for these patients.The Albanian population would benefit from Cystic Fibrosis neonatal screening, since outcomes can be improved through early diagnosis.

Clopidogrel, is a standard treatment in the prevention of major adverse cardiovascular events (MACE) in patients with coronary artery disease (CAD). Clopidogrel response is highly variable, mainly due to the presence of polymorphisms in the genes involved in drug metabolism. The aim of this study was to evaluate the association between the presence of the ABCB1 C3435T and CYP2C19*2 polymorphism and the clinical outcome in patients with CAD treated with clopidogrel. A total of 96 patients with CAD were included in the study. Genomic DNA from peripheral blood was extracted from all patients with standard phenol/chloroform protocol. The genotyping was performed by Real-Time PCR using TagMan assays. The frequency of the reduced-function allele, in both genes, was higher in patients with negative outcome (36.36% vs 21.15%). A negative clinical outcome and an increased risk for MACE was observed in patients with concomitant inheritance of the CYP2C19 *1/*2 and ABCB1 CT genotype vs patients with other genotypes (22.73% vs 9.62%; OR 3.455; 95% CI= [0.936-12.743], p=0.05722. A trend towards higher risk of MACE was also noted in carriers of the CYP2C19*1/*1 and ABCB1 CC/CT genotype. Our results support the data on the association of the CYP2C19 *2 alone, or in combination with the ABCB1 C polymorphism with the increased risk of MACE. The results also indicate that the presence of ABCB1 C343T polymorphism might be potentially considered as independent predictor of MACE in patients on clopidogrel. However, these results are preliminary and should be confirmed on a larger number of patients.

We present the findings of a Whole Exome Sequencing in a 2-year-old boy, conceived via In Vitro Fertilization with donor sperm, who suffers from an undiagnosed neurological syndrome. The following heterozygous variant in the EPHA4 gene was identified and classified as likely pathogenic: c.1655_1656, p.(Ser552CysfsTer23). Subsequent segregation analysis showed that the variant was not inherited from the mother and the sperm donor is not accessible for genetic testing. The presented results can further expand upon the genetic variants considered when diagnosing complex neurological syndromes and shows the importance of access to biological samples from donor banks in genetically ambiguous cases.

Raynaud-Claes syndrome is rare condition characterized with intellectual disability and is caused by X-linked pathogenic variants in CLCN4 gene. Hemizygous missense variant NM_001830.4: c.1597G>A (p.V533M) was detected in a 6-year-old male followed up with intellectual disability, dysmorphism, and epileptic encephalopathy. The mother and one sister of the patient were also carrying the same variant. The clinical picture of the patient was significantly more severe, and the patient exhibited nonconvulsive status. Tonic status was observed with benzodiazepine treatment and the patient was successfully treated with a ketogenic diet. Many types of seizures can be seen in Raynaud-Claes syndrome, some of which can be life-threatening. CLCN4 variants can be investigated in patients who exhibit an increase in tonic seizures with benzodiazepine treatment. However, ketogenic dietary therapy as first-line treatment can be lifesaving in resistant epilepsy cases caused by the CLCN4 gene.

Background: Almost 50% of NSCLC patients who initially show a successful response to tyrosine kinase inhibitors targeted therapy (TKI therapy) eventually develop acquired EGFR T790M mutation. The T790M secondary mutation can cause resistance to the targeted therapy and disease relapse. Since this mutation can be present at very low frequencies in liquid biopsy samples, droplet digital PCR (ddPCR), due to its high sensitivity, has opened the possibility for minimally invasive monitoring of the disease during TKI targeted therapy.

Materials and methods: For this study, a total of 45 plasma samples from NSCLC patients with previously detected EGFR-activating mutations were analyzed. Extracted circulating free DNA was amplified and examined for the presence of T790M mutation using ddPCR technology. For the data analysis, QuantaSoft Software was used.

Results: Of 45 tested plasma samples, a total of 14 samples were identified as positive for the T790M mutation. The same samples eventually showed the presence of T790M mutation in FFPE. Droplet digital PCR showed its great advantage in high sensitivity detection of rare allele variants. Our ddPCR assay detected T790M mutant allele in frequencies from 0.1%. The average number of droplets generated by ddPCR was 9571.

Conclusion: Monitoring of the T790M mutation has an important role in the examination of the effects of the prescribed TKI therapy. Since monitoring of potential changes during TKI therapy requires repeated sampling, our results showed that ddPCR technology has made it possible to use liquid biopsy as an adequate minimally invasive alternative for single nucleotide polymorphisms (SNP) detection.

Preimplantation genetic testing (PGT) is the earliest form of prenatal diagnosis that has become an established procedure for couples at risk of passing a severe genetic disease to their offspring. At UMC Ljubljana, we conducted a retrospective register-based study to present 15 years of PGT service within the public healthcare system in Slovenia. We collected the data of the PGT cycles from 2004 to 2019 and compared clinical outcomes for chromosomal and monogenic diseases using different embryo biopsy and testing approaches. In addition, we assessed the extent to which PGT has become the preferred option compared to classic prenatal diagnostics. We treated 211 couples, 110 with single gene disorder, 88 with structural chromosome rearrangement and 13 for numerical chromosome aberration. There were 375 PGT cycles with oocyte retrieval, while embryo transfer was possible in 263 cases resulting in 78 deliveries and 84 children. Altogether, the clinical pregnancy rate per embryo transfer was 31% in 2004-2016 (blastomere biopsy) and 43% in 2017-19 (blastocyst biopsy), respectively. We assessed that approximately a third of couples would opt for PGT, while the rest preferred natural conception with prenatal diagnosis. Our results show that providing a PGT service within the public healthcare system has become a considerable option in pregnancy planning for couples at risk of transmitting a severe genetic disease to their offspring. In Slovenia, approximately a third of couples would opt for PGT. Although the number of cycles is small, our clinical results are comparable to larger centres.