Mari Hachmeriyan

Although hematologic malignancies are mainly sporadic, an increasing number of cases result from an inherited predisposition. The current landscape of hematologic diagnostics includes next-generation sequencing and the integration of myeloid neoplasms with germline predisposition in the World Health Organization and International Consensus Classification. Identifying inherited hematologic malignancies is challenging because of overlapping somatic mutations, clonal hematopoiesis, varying penetrance, and acquired somatic genetic rescue. Constitutional genetic testing requires a thorough strategy. This includes choosing an optimal tissue sample to avoid contamination with malignant blasts or donor chimerism following transplantation. When multigene panels yield indeterminate results, orthogonal technologies, functional analyses, and reflex to exome or genome sequencing are essential. Molecular confirmation is crucial to apply genomics in clinical practice by avoiding unintended transplantations with donors who carry pathogenic variants, adjusting transplant conditioning to reduce toxicity in diseases with DNA repair defects and telomere biology abnormalities, and implementing surveillance and cascade screening based on the syndromes’ characteristics. This review highlights major hereditary hematologic malignancy syndromes, describes clinical alarm signs that warrant further investigation, and provides an algorithm for genetic and hematologic practice.

Background: Cancer predisposition syndromes (CPS) are increasingly recognized in pediatric oncology. In many cases, malignancy in children represents one manifestation of a broader genetic syndrome, often accompanied by dysmorphic features or other distinctive clinical findings. Methods: Clinical documentation and genetic test reports of pediatric patients evaluated over a six-year period (2020–2025) at a genetic counseling unit in a tertiary university hospital in Varna, Bulgaria, were retrospectively reviewed. Referral patterns, clinical characteristics, and genetic findings in children assessed for suspected CPS were analyzed. Results: In total, 430 children underwent genetic testing during the study period; among them, 42 fulfilled the criteria for CPS and were subsequently included in the analysis. Patients were categorized into three groups: those with malignancy (21.4%), those with high-risk hematologic/immune features without malignancy (9.5%), and those referred based on phenotypic features alone (69.0%). Most referrals originated outside oncology services, primarily from general pediatric clinics and outpatient settings, highlighting the importance of non-oncologists in early CPS recognition. Multisystem phenotypic features were common, with 69.0% of patients exhibiting involvement of two or more clinical domains. Genetic testing, predominantly using multigene panels and exome sequencing, identified clinically relevant variants in established CPS genes, most frequently in autosomal dominant conditions within this diagnosis-confirmed cohort. The most common diagnostic categories included NF1 spectrum disorders and RASopathies. Conclusions: These findings emphasize that CPS identification often relies on recognition of non-oncologic features rather than malignancy alone. Genetic counseling plays a central role in diagnosis, risk assessment, and cascade testing. Strengthening awareness among general pediatricians and improving access to genetic services are critical for optimizing early detection and prevention strategies.

Background: Primary renal Ewing sarcoma (ES) is an exceptionally rare and aggressive malignancy, posing significant diagnostic and therapeutic challenges in adults. Clinical presentation is often nonspecific, frequently resulting in delayed diagnosis and early metastatic dissemination. Methods: We report a case of a 45-year-old woman presenting with right lumbar pain and hematuria. Imaging included ultrasound and magnetic resonance imaging, revealing a well-demarcated multicystic lesion of the right kidney. Partial nephrectomy was performed, followed by histopathology, immunohistochemistry, and molecular analysis using fluorescence in situ hybridization to confirm ES breakpoint region 1 (EWSR1) rearrangement. Subsequent management included right nephrectomy and systemic chemotherapy following the vincristine, doxorubicin, cyclophosphamide/ifosfamide, etoposide (VDC/IE) protocol. Results: Histopathology demonstrated sheets of small round cells with Homer-Wright rosettes and strong membranous CD99 expression. Molecular testing confirmed EWSR1 rearrangement. The patient tolerated surgery and chemotherapy well, with no evidence of recurrence or metastasis at six-month follow-up. The case highlights the critical role of integrated imaging, histopathology, immunophenotyping, and molecular diagnostics in establishing the diagnosis of primary renal ES. Conclusion: Primary renal ES in adults requires a high index of suspicion, multidisciplinary evaluation, and personalized therapeutic strategies. Surgical resection combined with systemic chemotherapy can achieve disease control. Early recognition, molecular confirmation, and interdisciplinary coordination are essential to optimize outcomes in this rare malignancy.

Background/Objectives: Autism spectrum disorder (ASD) is a clinically and genetically heterogeneous neurodevelopmental condition, and the diagnostic yield of whole-exome sequencing (WES) varies across settings. This single-center study aimed to determine the molecular diagnostic yield of WES in pediatric ASD and to explore genotype–phenotype overlap using a structured, phenotype-driven reanalysis strategy. Methods: We enrolled 60 children with syndromic and non-syndromic ASD, who underwent detailed clinical and dysmorphology assessment. WES for single-nucleotide and copy-number variant (CNV) detection was performed in an accredited laboratory, followed by clinician-driven reinterpretation, integrating expanded phenotypic data and ACMG/AMP-based variant classification. Genes were considered if they harbored rare, potentially pathogenic variants and were previously reported or curated in established ASD-associated gene resources. Results: The initial external laboratory report identified 5 of 60 patients (8.3%) with a pathogenic (P) or likely pathogenic (LP) variant (positive result), 30 of 60 (50.0%) with a variant of unknown significance (VUS) (inconclusive result), and 25 of 60 (41.7%) with a negative result. Clinician-based variant reinterpretation identified pathogenic or likely pathogenic variants in 9 of 60 patients (15.0%), representing an 80% relative increase in diagnostic yield, as well as 43 VUSs distributed across 34 patients, while 17 patients had no reportable variants (negative result). Overall, reanalysis revealed 11 additional variants of interest (pathogenic, likely pathogenic, or VUS) that had not been reported in the initial assessment. In total, 52 sequence and copy-number variants in 46 genes were detected, most of which were VUSs (83%). Conclusions: In this pediatric ASD cohort, WES with phenotype-driven reinterpretation and CNV assessment yielded a clinically positive result in 15% of patients and uncovered additional candidate variants, highlighting both the value and the current interpretative challenge of comprehensive genomic testing in ASD.

Background and Clinical Significance: Kidney transplant recipients have a 2–4-fold higher cancer risk than the general population. The sequential occurrence of multiple myeloma (MM) and native-kidney renal cell carcinoma (RCC) is rare and creates competing priorities between anti-myeloma efficacy and allograft preservation. Case Presentation: A 54-year-old woman with a 2020 living-donor kidney transplant presented in 2024 with bone pain and shoulder swelling. Low-dose whole-body CT showed multiple punched-out osteolytic lesions. Work-up revealed IgG-κ M-protein 38.5 g/L and 25% clonal plasma cells; cytogenetics showed a complex karyotype (R-ISS III). First-line bortezomib/cyclophosphamide/dexamethasone (VCd) was given while maintaining tacrolimus plus low-dose steroid. After four cycles, she achieved very good partial response (M-protein 42.3 to 5.6 g/L) with stable graft function. Follow-up imaging detected a large exophytic mass in the native right kidney; nephrectomy confirmed papillary RCC, type II. Later, the myeloma progressed with epidural extension causing cord compression. Second-line daratumumab/carfilzomib/dexamethasone (DKd) and palliative spine radiotherapy were initiated. The course was complicated by opportunistic infection and pancytopenia, and the patient died in January 2025. Conclusions: Vigilant post-transplant cancer surveillance—including native-kidney RCC—tailored immunosuppression, and multidisciplinary coordination are critical. VCd with tacrolimus may be feasible when graft preservation is prioritized; however, relapsed high-risk MM on DKd carries substantial infectious risk and a guarded prognosis.

Background/Objectives: Genetic abnormalities are critical for the diagnosis, prognosis, and therapeutic management of myelodysplastic syndromes (MDS). This study aims to evaluate the clinical utility of Multiplex Ligation-dependent Probe Amplification (MLPA) as a rapid and cost-effective method, determining its place alongside Next-Generation Sequencing (NGS) for the initial genetic assessment of patients with MDS. Methods: Bone marrow samples from 68 patients newly diagnosed with MDS were analyzed. Genomic DNA was investigated using the SALSA MLPA P414-C1 MDS probe mix to detect common copy number variations (CNVs). Results: MLPA detected genetic variants in 25 patients (36.8%). The most common finding was a single chromosomal abnormality (26.5%). Multiple pathological findings were observed in only 1.5% of patients, and a JAK2 mutation was observed in 8.8% of the cohort. However, the presence of these aberrations did not show a statistically significant association with overall survival (OS) in the cohort. Patient sex was identified as the only variable that was associated with a marginal level of statistical significance regarding OS, indicating a worse prognosis for males. Conclusions: MLPA is a valuable, rapid, and cost-effective tool for initial genetic screening in low-resource settings. This was highlighted by our finding that sex was the sole significant prognostic factor, while the MLPA-detected variants were not found to be significant. The findings suggest that comprehensive risk stratification aligned with international standards requires more advanced molecular technologies.

The genetic diversity of acute myeloid leukemia creates a major obstacle for current research and clinical practice. Despite advances in molecular genetic techniques, various omics approaches, and artificial intelligence, developing a universal algorithm to thoroughly assess each clinical case remains difficult. Starting with current recommendations and classifications, this narrative review highlights the most important diagnostic options available today, new opportunities that are emerging, and the challenges in diagnosing and managing this complex disease.

Background: Huntington’s disease (HD) is a progressive, autosomal dominant neurodegenerative disorder caused by an expanded CAG repeat in the HTT gene. Despite advances in understanding its molecular basis, epidemiological data in many countries, including Bulgaria, remain limited. This study aims to present clinical and genetic findings from a 20-year single-centre cohort. Methods: A retrospective review was conducted of patients evaluated for HD at the University Hospital “St. Marina” in Varna between 2004 and 2024. Data included demographics, CAG repeat length, clinical features, imaging, and psychiatric assessments. Statistical analysis focused on correlations between variables, with significance set at p < 0.05. Results: Out of 79 referred individuals, 43 were molecularly confirmed. The mean age of onset was 43 years, with a four-year diagnostic delay. The average CAG repeat length was 44.6, though two symptomatic patients had reduced penetrance alleles (38 and 39 repeats). Cognitive and psychiatric symptoms were each present in 72% of cases. Depression was significantly more prevalent in women (p = 0.011). Most patients had a positive family history, predominantly maternal. Conclusions: Our findings highlight diagnostic delays, gender-specific psychiatric vulnerabilities, and the importance of personalized care. Improved access to genetic counselling and early diagnosis are essential for optimizing outcomes.

Background: Next-generation sequencing (NGS), particularly whole-exome sequencing (WES), has become a powerful diagnostic tool for rare genetic conditions. However, its success rate varies based on the underlying genetic etiology and the population studied. Methods: This retrospective study evaluated the diagnostic yield of NGS in a cohort of 137 pediatric patients with suspected rare genetic disorders in Bulgaria, a setting where such testing is not reimbursed and must be self-funded. The patients underwent either WES or targeted gene panel testing based on clinical presentation, family history, and genetic evaluation. Results: The overall diagnostic yield was 45.99%, with WES achieving 51.25% and targeted testing achieving 38.60%. The highest yield was observed in patients presenting with both dysmorphic features and neurodevelopmental delays (62.5%), while the lowest was observed among those with isolated neurodevelopmental issues (10%). A significant portion of the identified variants (35.9%) were novel. Eight patients were diagnosed with copy number variants (CNVs) detected only through WES. Conclusions: Our findings illustrate the value of WES as a first-line test and highlight the impact of deep phenotyping on diagnostic success. This study also emphasizes the need for a population-specific reference genome and equal access to genomic diagnostics in all European countries.

Background and Clinical Significance: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder caused by mutations in the CYP27A1 gene, leading to impaired bile acid synthesis and systemic cholesterol deposition. The condition presents with a broad spectrum of symptoms affecting multiple organs and systems, including the eyes, central nervous system, tendons, and skeletal muscles. Due to its heterogeneous and often ambiguous clinical manifestations, CTX is frequently misdiagnosed or remains undiagnosed for years. Case Presentation: We report the case of a 37-year-old male who was admitted to our university hospital with a long-standing history of progressive muscle weakness in the arms and legs. His medical history revealed bilateral cataract surgery in childhood, cognitive decline, epilepsy, and bilateral round swellings of the Achilles tendons, suspected to be xanthomas. A clinical diagnosis of CTX was established, and sequencing analysis confirmed the presence of a homozygous pathogenic variant in the CYP27A1 gene. Despite the unavailability of chenodeoxycholic acid (CDCA) therapy in Bulgaria, symptomatic management was provided. Conclusions: This case underscores the diagnostic challenges associated with CTX and highlights the prolonged diagnostic journey faced by patients with rare neurogenetic disorders. It also emphasizes the need for increased awareness and early recognition of such conditions to improve patient outcomes.