Balkan Journal of Medical Genetics最新文献

The discordance rate of the results between immunohistochemistry (IHC) and molecular microsatellite instability (MSI-PCR) tests, the most commonly used methods for qualitative deficient mismatch repair (dMMR) testing, is 1-10%, highlighting the need for a more precise testing strategy. The next-generation sequencing (NGS) offers a more sensitive and effective dMMR analysis (MSI-NGS), which also provides quantitative data. The aim of the study was to evaluate the qualitative and quantitative aspects of IHC and MSI-PCR testing compared to MSI-NGS in detecting dMMR in patients with Lynch Syndrome (LS)-associated and sporadic colorectal (CRC) and endometrial cancers (EC). Our results demonstrate both qualitative and quantitative discrepancies in the results obtained with different methods. Regarding qualitative differences, dMMR was inadequately interpreted only in LS when relying solely on IHC or MSI-PCR testing. This was primarily due to the specific mutational profile in our population, indicating the need for the implementation of a specific strategy that combines both methods. Concerning the quantitative differences, we detected great variability in the MSI levels, which was partly attributed to the tissue type or to the type of mutation in LS patients. Our results suggest that MSI-NGS level could be used as a potential surrogate marker for neoantigen levels and provide more precise predictive information for immunotherapy in patients with dMMR deficiency.

Background: Reciprocal translocations are one of the most common structural chromosomal rearrangements in humans, they are due to the exchange of chromosome material between two nonhomologous chromosomes.If a person carries a balanced reciprocal translocation, meiosis may produce normal gametes, as well as gametes with either balanced or unbalanced abnormalities, depending on the segregation pattern during gametogenesis. All types of segregations can occur, although with different percentages. The adjacent-2 segregation is the less common one and it often leads to non-viable products in many species.

Case presentation: We report a case of an 18 months-old female patient, who was referred to the medical genetics' consultation for psychomotor retardation and facial dysmorphism. A postnatal constitutional karyotype was performed in our laboratory on a peripheral blood sample followed by a parental karyotype. The results revealed an additional derivative chromosome 9 in the patient resulting from an adjacent-2 segregation in the mother.

Conclusion: This observation highlights the possible occurrence of rare mechanisms of segregation during meiosis in families with a reciprocal translocation. Investigating these events is crucial for both diagnosis and genetic counseling.

The purpose of our study is to expedite cancer diagnosis through the development of software for rapid detection of hereditary breast cancer (BC) with negative BRCA1/2 on MATLAB, utilizing a fuzzy logic system with several variants of genes associated with BC. This system serves as a clinical decision-support tool, assisting in early classification and interpretation of genetic variants by combining clinical and genetic data. Clinical data were obtained from Erciyes University Faculty of Medicine Department of Medical Genetics and Uludağ University Faculty of Medicine Department of Medical Genetics. 488 individuals were studied. Only 90 of them were relevant to our investigation since their BRCA1/2 genes did not exhibit notable genetic mutations. We examined 16 distinct breast cancer risk factors and focused on mutations related to 18 hereditary BC genes. The collected data were integrated into the developed system, and various membership functions were given varying degrees of possibility, ranging from 0 to 1, depending on their participation in input clusters. After the system was trained on 90 cases and validated on six independent patients, its accuracy was assessed, yielding reliable results. Following the training phase, outcomes revealed the presence of two pathogenic variants at 0.92 (92%), two benign variants at 0.25 (25%), and two variants of unknown significance at 0.5 (50%). Given the high incidence of breast cancer, early prediction is paramount. Despite the emergence of fuzzy logic systems in medical applications, limited research akin to our study exists. The establishment of this artificial intelligence software holds promise for advancing the early detection of BC in future clinical applications.

Objective: Colorectal cancer is the third most common malignancy in the world and among the most frequent causes of cancer-related death. Our study aimed to evaluate the molecular profile of the patients diagnosed with colorectal carcinoma at Clinical Hospital Acibadem-Sistina in Skopje.

Materials and methods: This study is retrospective-prospective, conducted at the Department of histopathology and cytology, at Clinical Hospital Acibadem-Sistina in Skopje. Tissue samples from surgical material from 152 patients diagnosed with CRC were processed for molecular and immunohistochemical analysis. KRAS and BRAF mutations were analyzed, and MMR status was obtained. In 90 metastatic cases, evaluation of HER2 and PDL-1 expression was performed on a tissue microarray.

Results: Among 152 analyzed patients diagnosed with colorectal carcinoma, the majority were males (98, 64.47%) compared to females (54, 35.53%). The mean age was 68.4±11.3 years; the median age was 70 years. KRAS/NRAS mutations were detected in 47(31%) of patients, BRAF mutations in 11(7%) patients, and mismatch repair gene deficiency (MMRd) was found in 15(10%) of patients. HER2 positive expression was present in 36(40%) of patients, and 17(19%) of patients showed PDL-1 expression. In the group of 17 PDL1-positive tumors, a cutoff of more than 1% positive tumor cells was detected in 10 cases, more than 10% tumor cells in 4 cases, and more than 50% tumor cells in 3 cases. From 36 HER2 positive cases, 32(32,5%) were with score 2+, and 4(4,4%) with score 3+.

Conclusions: Continued research into molecular mechanisms and biomarkers holds the promise of further improving CRC outcomes through personalized and effective interventions.

Over the past five years, the MYCBP2 has emerged as a potential candidate gene associated with neurodevelopmental disorders (NDDs). In 2023, a newly characterized condition, termed MYCBP2-related developmental delay with corpus callosum defects (MDCD), has been reported in eight individuals presenting corpus callosum abnormalities, developmental delay, intellectual disability, epilepsy and autistic features. To date, all reported cases have been associated with distinct de novo variants. Here, we describe the first family with three affected members carrying a novel pathogenic MYCBP2 variant. A mother and her two sons were referred to our laboratory for genetic testing. The phenotypic characteristics of our three patients included intellectual disability, speech impairment, facial dysmorphism, microcephaly and seizures (presented only in the mother). We performed WES on the three affected family members using Twist Human Core+RefSeq+Mitochondrial Panel on Illumina Nova Seq 6000. We have identified a novel loss of function variant in MYCBP2 [NM_015057.5 c.7311del, p.(Leu2438Trpfs*3)] in heterozygous state in the mother and her two sons. The variant causes a frameshift, leading to NMD and C-terminal truncation, eliminating key domains (RING and TC) essential for ubiquitin ligase activity and interactions with other cellular components, particularly in processes related to synaptic regulation. Here, we present the clinical manifestation of MYCBP2-related developmental delay in three patients of a same family. Our study further supports the critical role of MYCBP2 in the pathogenesis of NDDs and contributes to the phenotype of a recently recognized MDCD syndrome.

X-linked adrenoleukodystrophy (X-ALD) is a fatal neurodegenerative disorder caused by mutations in the adenosine triphosphate-binding cassette D1 (ABCD1) gene. In this study, we report the case of a Moroccan patient diagnosed with X-ALD due to a mutation in the ABCD1 gene. This diagnosis enabled a genetic counseling with presymptomatic analysis of the disease in the patient's brother, facilitating proactive management for the family. This work expands the clinical and genetic spectrum of XALD and underscores the critical role of presymptomatic testing in the management of neurodegenerative diseases.

Monoallelic KIF11 variants are associated with Microcephaly with or without Chorioretinopathy, Lymph-edema, or Impaired Intellectual Development (MCLMR) (OMIM:152950). This study presents seven patients from two distinct families, exhibiting extreme clinical heterogeneity, along with novel clinical findings and genetic variants. Patient 1 presented with learning difficulties, epilepsy, behavioral abnormalities, and various ocular anomalies, in addition to microcephaly and facial dysmorphism. Patient 2 was prenatally diagnosed with dorsal pedal edema, which was confirmed postnatally, alongside facial dysmorphic features and the need for craniosynostosis surgery at four months. Peripheral blood samples were obtained for DNA isolation, and Whole Exome Sequencing (WES) was performed for molecular analysis. Whole-exome sequencing (WES) revealed a de novo heterozygous frameshift variant in the KIF11 gene (NM_004523.4: c.2224_2225del; p. Asn742TyrfsTer6) in patient 1, and a novel heterozygous frameshift variant (NM_004523.4: c.2946dup; p. Leu983SerfsTer6) in the same gene in patient 2. Segregation analysis demonstrated that Patient 2's variant was inherited from the mother and was also present in the maternal grandmother, sister, and two aunts. Our findings highlight the broad clinical heterogeneity of MCLMR syndrome, as Patient 1 exhibited keratoconus, optic nerve hypoplasia, behavioral problems, and seizures, which are rarely reported. Additionally, Patient 2 represents the first documented patient of prenatal lymphedema detection in MCLMR syndrome. Furthermore, craniosynostosis, identified in two patients (P2 and P5), has not been previously described, suggesting a potential novel phenotypic feature. These findings expand the genotypic and phenotypic spectrum of KIF11-related disease.

Miscarriage, defined as the spontaneous loss of a fetus before viability, is the most common complication of pregnancy. Among its many causes, genetic factors are thought to play a significant role. One of the key signaling pathways involved in embryonic development is the Wnt/β-catenin pathway, which regulates critical processes such as embryonic cell migration, cell fate determination, proliferation, and differentiation. This pathway is also essential for early developmental events, including preimplantation development and blastocyst implantation. Although numerous animal studies have linked disruptions in Wnt signaling to pregnancy loss, limited data exist on its role in human miscarriage. In this study, we aimed to investigate the expression profiles of genes involved in the Wnt/β-catenin signaling pathway in placental tissues from a total of 23 miscarriage cases, including 15 with normal and 8 with abnormal fetal karyotypes. Our analysis revealed that GSK3B, WNT3A, WNT4, AXIN2, and APC were upregulated in the normal karyo-type group, while CTNNB1 (β-catenin) and WNT5A were downregulated. DVL1 expression showed no significant difference between the groups. These findings suggest that upregulation of GSK3B, AXIN2, and APC, together with downregulation of β-catenin, may lead to inhibition of the Wnt/β-catenin signaling pathway. Such disruption could impair key cellular processes-including proliferation, migration, and blastocyst implantation-that are essential for early pregnancy maintenance.

Introduction: The aim of this study was to compare the frequency of rs1205, rs1130864 and rs1800947 single nucleotide polymorphisms (SNPs) in the C-reactive protein (CRP) gene in rheumatoid arthritis (RA) patients and healthy controls. In addition, the aim was to investigate the association between these polymorphisms and serum CRP levels, Disease Activity Score-28 (DAS28) and clinical findings, especially extra-articular involvement such as interstitial lung disease.

Methods: This single-center study included 120 patients with RA and 100 healthy controls. DAS28-CRP was used to measure disease activity. Interstitial lung disease was confirmed by ground-glass opacities and interstitial thickening on chest computed tomography (CT) and other CT findings. Peripheral blood samples were collected in tubes with EDTA for genotyping. After DNA extraction, SNPs were analyzed using TaqMan probe-based polymerase chain reaction.

Results: Among the three CRP SNPs (rs1130864, rs1205, rs1800947), a significant difference was observed in the distribution of rs1130864 between RA patients and controls. TT homozygous and CT heterozygous genotypes were significantly lower in the patient group (p = 0.002). Furthermore, the TT genotype of rs1130864 was significantly associated with lung involvement in patients with RA (p = 0.017). No significant association was found between SNPs and baseline CRP levels and DAS28 scores.

Conclusion: In our study, we found a significant association between CRP rs1130864 gene polymorphism and lung involvement in RA patients. To the best of our knowledge, this is the first study to evaluate this association. However, further studies with larger cohorts are needed to confirm these findings.

Cystinuria is a rare, lifelong, autosomal recessive disorder characterized by high urine cystine excretion, leading to chronic and recurrent kidney stone formation. This inherited metabolic disorder occurs due to defective cystine, lysine, ornithine, and arginine reabsorption in the brush border membrane of the proximal renal tubule (S3 segment) and the gastrointestinal epithelial cells. Tiopronin is a thiol agent used in the treatment of severe homozygous cystinuria in patients who are resistant to conservative measures. We report an 18-year-old male with cystinuria confirmed by genetic testing, who was treated with conservative measures such as high fluid intake, low sodium diet, and oral potassium citrate since the diagnosis was made at four years of age. However, due to the recurrence of several calculi in both kidneys, tiopronin treatment was initiated at the dose of 250 mg three times a day. After three months of therapy, the patient developed nephrotic syndrome with proteinuria of 6.6 g/l, hypoproteinemia, hyperlipidemia, and edema. Considering the adverse effect of tiopronin, the drug was immediately withdrawn and the patient was managed with human albumin substitution, diuretics, and angiotensin receptor blocker, without corticosteroids. Complete clinical and biochemical remission was achieved within 7 days. Clinicians should be aware of this rare but serious adverse effect of tiopronin, and monitor patients receiving tiopronin carefully for the possible occurrence of edema, proteinuria, with the aim of timely intervention and tiopronin discontinuation.