1. Spectrum of genetic variants and yield of genetic testing in Slovenian probands with suspected cardiomyopathies surviving sudden cardiac arrestNina Vodnjov, Aleš Maver, Borut Peterlin, Karin Writzl, 2025, izvirni znanstveni članek Povzetek: Abstract Background Cardiomyopathies (CMs) present phenotypically on a spectrum and in a proportion of patients the initial presentation is sudden cardiac arrest (SCA). Studies performing genetic screening of SCA survivors have identifed (likely) pathogenic (LP/P) variants in 2–50% of probands, with mean cohort ages ranging from 28 to 64 years. Due to inconsistent data in the literature, our study aimed to genetically characterise Slovenian SCA survivors with clinically confrmed/suspected cardiomyopathy (CM). The present study included 29 probands (17 women, 59%) with clinically confrmed/suspected CM who survived SCA and were referred to the Clinical Institute of Genomic Medicine for genetic testing between January 2010 and July 2024. The majority of probands (23; 79%) underwent whole exome sequencing, and the remainder either clinical exome (5; 17%) or panel sequencing (1; 4%). Genetic data were analysed following ACMG/AMP guidelines and ACGS recommendations. Results Probands survived SCA at a mean age of 49±17 years (range 15–71), and 12 (41%) were<50 years old. The majority had clinically confrmed/suspected arrhythmogenic (10; 34.5%) or dilated (9; 31.0%) CM, while the remainder had clinically undefned (5; 17.2%), hypertrophic (4; 13.8%), or non-compaction (1; 3.4%) CM. Seven LP/P variants in CM-related genes were identifed in eight (28.6%) probands. In addition, 16 variants of uncertain signifcance (VUS) were identifed in 12 (41.3%) probands. Probands’ age at SCA did not signifcantly afect the yield, as LP/P variants were identifed in four probands<50 years at SCA and in four>50 years (p=0.56), nor did the positive family history of heart disease (p=0.55) or sudden cardiac death (p=0.43). There were also no signifcant diferences in probands’ age and test outcome, as the mean age of patients with LP/P variants was 46±21 years, those with the VUS(s) were 45±15 years, and those without candidate variant(s) were 55±12 years (p=0.41). Conclusions LP/P variants were identifed in almost one-third of Slovenian SCA survivors with clinically confrmed/ suspected CM. Genetic testing of SCA survivors with structural clinical fndings provides additional confrmation of the clinical diagnosis and a basis for identifying relatives at risk of heart disease, allowing for better management.
Ključne besede: sudden cardiac arrest, genetic testing, molecular pathology, (likely) pathogenic variants, hereditary cardiomyopathy
Objavljeno v DiRROS: 10.04.2026; Ogledov: 152; Prenosov: 70
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2. Palliative care for children and adults with inherited metabolic disease in Europe : an underutilised service for supportive treatment and careAnja Lee, Yngve Thomas Bliksrud, Michela Onali, Julia Neugebauer, Francois Eyskens, 2025, izvirni znanstveni članek Povzetek: Palliative care should be an integral part of follow-up for patients with life-limiting/life-threatening conditions, irrespective of age and diagnosis. Many patients with inherited metabolic disorders (IMD) have palliative care needs due to multi-systemic conditions without curative treatment options. To map the organisation and accessibility of palliative care across European IMD expert centres, and to explore the experiences of IMD physicians with palliative care, the European Reference Network for Hereditary Metabolic Disorders (MetabERN) invited physicians from all 103 member institutions to participate in a survey covering various aspects of palliative care. Ninety-two physicians from 63 institutions in 23 countries participated. A national plan or strategy for palliative care had been established in most countries (87%). Both children (91%) and adults (89%) had access to palliative care services. Most paediatric (86%) and many adult IMD physicians (67%) used advance care planning. A total of 284 referrals to palliative care were reported, mostly IMD patients with lysosomal and mitochondrial disorders, and neurological, respiratory, cognitive and gastrointestinal comorbidities. However, during the past 5 years, the majority of physicians (60%) had referred 20% or fewer of their deceased patients to palliative care. Although palliative care is available in most European IMD expert centres, only a small proportion of deceased IMD patients has been referred. The findings of this study indicate both a misconception and underutilisation of modern palliative care services. Addressing existing barriers is essential, and both IMD physicians and patients may need more information about available palliative care services and up-to-date indications for referral.
Ključne besede: palliative care, quality of life, patients, paediatric palliative care, inherited metabolic diseases, genetic disorders, MetabERN, The European Reference Network for Hereditary Metabolic Disorders
Objavljeno v DiRROS: 11.12.2025; Ogledov: 382; Prenosov: 248
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3. Novel ATP7A splice-site variant causing distal motor neuropathy and occipital horn syndrome: two siblings and literature reviewKarin Writzl, Maruša Škrjanec Pušenjak, Matevž Jus, Aleš Maver, Nuška Pečarič-Meglič, Borut Peterlin, Lea Leonardis, 2025, izvirni znanstveni članek Povzetek: Background: Pathogenic hemizygous variants in ATP7A most commonly cause Menkes disease or occipital horn syndrome (OHS), whereas ATP7A-related distal hereditary motor neuropathy (dHMN) is rarely reported. Here, we describe two adult brothers with an overlapping dHMN/OHS phenotype caused by a novel ATP7A splice-site variant and review the clinical and genetic features of previously published patients with ATP7Arelated dHMN. Methods: We performed detailed clinical, electrophysiological, and genetic evaluations of both siblings, including exome sequencing and RNA analysis. Additionally, we reviewed the clinical, electrophysiological, and genetic data of previously reported patients with ATP7A-related dHMN. Results: We identified a novel hemizygous ATP7A splice-site variant (NM_000052.7:c.1544-2A>T) in both brothers. The younger brother, who exhibited a more severe phenotype, presented in early childhood with mild global developmental delay, intellectual disability, and chronic diarrhea, while the older brother had childhood-onset chronic diarrhea without cognitive impairment. Both developed distal hereditary motor neuropathy later in life, and imaging revealed occipital horns. Serum copper and ceruloplasmin levels were mildly reduced. RNA sequencing revealed two aberrant transcript isoforms resulting from the splice-site variant, one of which may produce a partially functional protein. Review of previously reported patients shows that ATP7A-related dHMN may occur isolated or with overlapping features of OHS. In patients with the overlapping phenotype, chronic diarrhea was often the first symptom, followed by slowly progressive dHMN. Conclusions: Previously reported ATP7A-related dHMN has been mostly associated with missense variants. Our findings expand the mutational spectrum by identifying a splice-site variant. In patients with an overlapping OHS/dHMN phenotype, diagnosis was typically delayed for decades, suggesting this presentation remains underdiagnosed.
Ključne besede: ATP7A, splice-site variant, distal hereditary motor neuropathy, occipital horn syndrome, copper metabolism, neurogenetics
Objavljeno v DiRROS: 05.12.2025; Ogledov: 768; Prenosov: 231
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4. Oral Coenzyme Q10 supplementation leads to better preservation of kidney function in steroid-resistant nephrotic syndrome due to primary Coenzyme Q10 deficiencyStefania Drovandi, Beata Lipska-Zietkiewicz, Fatih Ozaltin, Francesco Emma, Bora Gülhan, Olivia Boyer, Agnes Trautmann, Hong Xu, Tanja Kersnik-Levart, 2022, izvirni znanstveni članek Povzetek: Primary Coenzyme Q10 (CoQ(10)) deficiency is an ultra-rare disorder caused by defects in genes involved in CoQ(10) biosynthesis leading to multidrug-resistant nephrotic syndrome as the hallmark kidney manifestation. Promising early results have been reported anecdotally with oral CoQ(10) supplementation. However, the long-term efficacy and optimal prescription remain to be established. In a global effort, we collected and analyzed information from 116 patients who received CoQ(10) supplements for primary CoQ(10) deficiency due to biallelic pathogenic variants in either the COQ2, COQ6 or COQ8B genes. Median duration of follow up on treatment was two years. The effect of treatment on proteinuria was assessed, and kidney survival was analyzed in 41 patients younger than 18 years with chronic kidney disease stage 1-4 at the start of treatment compared with that of an untreated cohort matched by genotype, age, kidney function, and proteinuria. CoQ(10) supplementation was associated with a substantial and significant sustained reduction of proteinuria by 88% at 12 months. Complete remission of proteinuria was more frequently observed in COQ6 disease. CoQ(10) supplementation led to significantly better preservation of kidney function (5-year kidney failure-free survival 62% vs. 19%) with an improvement in general condition and neurological manifestations. Side effects of treatment were uncommon and mild. Thus, our findings indicate that all patients diagnosed with primary CoQ(10) deficiency should receive early and life-long CoQ(10) supplementation to decelerate the progression of kidney disease and prevent further damage to other organs.
Ključne besede: coenzyme Q10, deficiency, supplementation therapy, end-stage kidney disease, ESKD, genetic kidney disease, hereditary, kidney survival, outcome, proteinuria reduction
Objavljeno v DiRROS: 21.11.2025; Ogledov: 440; Prenosov: 243
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5. The toll walk transit function of a graph: axiomatic characterizations and first-order non-definabilityManoj Changat, Jeny Jacob, Lekshmi Kamal K. Sheela, Iztok Peterin, 2026, izvirni znanstveni članek Povzetek: A walk $W=w_1w_2\dots w_k$, $k\geq 2$, is called a toll walk if $w_1\neq w_k$ and $w_2(w_{k-1})$ are the only neighbors of $w_1(w_k)$ on $W$ in a graph $G$. A toll walk interval $T(u,v)$, $u,v\in V(G)$, contains all the vertices that belong to a toll walk between $u$ and $v$. The toll walk intervals yield a toll walk transit function $T:V(G)\times V(G)\rightarrow 2^{V(G)}$. We represent several axioms that characterize the toll walk transit function among chordal graphs, trees, asteroidal triple-free graphs, Ptolemaic graphs, and distance hereditary graphs. We also show that the toll walk transit function can not be described in the language of first-order logic for an arbitrary graph.
Ključne besede: toll walk, transit function, axioms, chordal graphs, AT-free graphs, Ptolemaic graphs, distance-hereditary graphs
Objavljeno v DiRROS: 24.09.2025; Ogledov: 403; Prenosov: 238
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6. Hereditary α − tryptasemia and peripheral blood KIT D816V mutation in patients with pediatric mastocytosisOlga Točkova, Tanja Planinšek Ručigaj, Simona Ivančan, Urška Bidovec, Matija Rijavec, Julij Šelb, 2025, izvirni znanstveni članek Povzetek: Hereditary α-tryptasemia (HαT)—a genetic trait caused by increased α-tryptase-encoding typtase alpha/beta-1 (TPSAB1) copy number—is associated with adult mastocytosis. The primary objective was to assess the association between α-tryptase and pediatric mastocytosis. We also want to evaluate whether the KIT p.D816V mutation in peripheral blood leukocytes (PBLs) reliably predicts systemic mastocytosis (SM) in children. A prospective cohort of 68 children from a referral center in Slovenia with cutaneous mastocytosis (CM) underwent tryptase genotyping by droplet digital PCR and examination for KIT p.D816V in PBL using a sensitive PCR test. A significant majority of patients (57 of 68; [83.8%]) had at least one α-tryptase-encoding gene; none had HαT. 7 of the 68 (10.3%) who were positive for KIT p.D816V in PBL, one fulfilled diagnostic criteria for indolent SM, and another was diagnosed with monoclonal mast cell activation syndrome. One of those individuals had an increased basal serum tryptase (BST) level (14.5 ng/mL). We found a high presence of germline α-tryptase in children with CM, but not HαT. By employing sensitive examination for KIT p.D816V in PBL, in combination with clinical data and other examinations, our study suggests that KIT p.D816V in PBL may indicate systemic disease in children with CM.
Ključne besede: KIT D816V, hereditary α-tryptasemia, peripheral blood
Objavljeno v DiRROS: 05.08.2025; Ogledov: 716; Prenosov: 474
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7. Hereditary α-tryptasemia is associated with anaphylaxis to antibiotics and monoclonal antibodiesPeter Korošec, Jonathan J. Lyons, Manca Svetina, Monika Koudová, Martina Bittóová, Mihaela Zidarn, Lenka Sedláčková, Matija Rijavec, Peter Kopač, 2025, izvirni znanstveni članek Povzetek: Background
Hereditary α-tryptasemia, a genetic trait caused by increased α-tryptase copy number, is associated with idiopathic and venom anaphylaxis.
Objective
We aimed to determine the impact of tryptase genotypes on drug-induced anaphylaxis.
Methods
A prospective discovery cohort of 99 patients from a referral center in Slovenia with acute anaphylaxis to drugs underwent tryptase genotyping by droplet digital PCR. For validation, we included a cohort of 26 patients from the Czech Republic. Associated inciting agents and the severity of the reactions were subsequently examined.
Results
Hereditary α-tryptasemia was associated with drug-induced anaphylaxis with a prevalence of 13% (n = 13 of 99) in the discovery cohort and 15% in the validation cohort (n = 4 of 26). Hereditary α-tryptasemia was identified in every individual with elevated basal serum tryptase levels (11.6-21.9 ng/mL; n = 14) within both cohorts of patients. Hereditary α-tryptasemia was more prevalent in individuals with antibiotic- or mAb-induced anaphylaxis in both the discovery and validation cohorts (n = 13 of 51; 26%) compared to those with anaphylaxis resulting from neuromuscular blocking agents, nonsteroidal anti-inflammatory drugs, contrast, chlorhexidine, or other drugs (n = 5 of 74; 7%; P = .02; odds ratio = 4.1; 95% CI, 1.3-11.1). Overall, we found fewer individuals with no ⍺-tryptase than in the general population, and there was a trend for subjects with more ⍺-tryptase copies to have more severe reactions. Thus, among subjects with three ⍺-tryptase copies, the prevalence of severe anaphylaxis was 73%, compared with 59% with one to two ⍺-tryptase copies and 58% for subjects without ⍺-tryptase.
Conclusions
Risk for anaphylaxis to antibiotics and biologics is associated with inherited differences in α-tryptase–encoding copies at Tryptase α/β1 .
Ključne besede: immunology, drug allergy, anaphylaxis, antibiotics, monoclonal antibodies, α-tryptase, hereditary α-tryptasemia
Objavljeno v DiRROS: 18.06.2025; Ogledov: 718; Prenosov: 414
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8. Cold-induced anaphylaxis : new insights into clinical and genetic characteristicsMojca Bizjak, Peter Korošec, Mitja Košnik, Julij Šelb, Urška Bidovec, Manca Svetina, Samo Zver, Dejan Dinevski, Matija Rijavec, 2025, izvirni znanstveni članek Povzetek: The pathogenesis of cold urticaria (ColdU) and cold-induced anaphylaxis (ColdA) remains poorly understood, and ColdA is underrepresented in anaphylaxis literature. Laboratory features to guide management are largely unknown. This study evaluated basal serum tryptase (BST) and total immunoglobulin E (IgE) levels in ColdU and ColdA, their associations with clinical features, and the utility of testing for the KIT p.D816V variant in blood leukocytes and hereditary a-tryptasemia (HaT).
Ključne besede: anaphylaxis, cold urticaria, hereditary α-tryptasemia, KIT p.D816V, mast cell, total IgE, tryptase
Objavljeno v DiRROS: 21.05.2025; Ogledov: 897; Prenosov: 438
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9. Finding a largest-area triangle in a terrain in near-linear timeSergio Cabello, Arun Kumar Das, Sandip Das, Joydeep Mukherjee, 2025, izvirni znanstveni članek Povzetek: A terrain is an $x$-monotone polygon whose lower boundary is a single line segment. We present an algorithm to find in a terrain a triangle of largest area in $O(n\log n)$ time, where $n$ is the number of vertices defining the terrain. The best previous algorithm for this problem has a running time of $O(n^2)$.
Ključne besede: terrain, inclusion problem, geometric optimisation, hereditary segment tree
Objavljeno v DiRROS: 12.03.2025; Ogledov: 742; Prenosov: 438
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10. High burden of clonal mast cell disorders and hereditary ▫$α-tryptasemia$▫ in patients who need Hymenoptera venom immunotherapyPeter Korošec, Gunter Sturm, Jonathan J. Lyons, Tinkara Pirc Marolt, Manca Svetina, Mitja Košnik, Mihaela Zidarn, Mark Kačar, Nina Frelih, Nika Lalek, Ajda Demšar Luzar, Samo Zver, Matevž Škerget, Ewa Czarnobilska, Wojciech Dyga, Sanja Popović-Grle, Miroslav Samaržija, Lisa Arzt-Gradwohl, Urban Čerpes, Grzegorz Porebski, Branko Pevec, Eva Schadelbauer, Peter Kopač, Julij Šelb, Matija Rijavec, 2024, izvirni znanstveni članek Povzetek: Background
In patients who require venom immunotherapy (VIT), there is a need to identify underlying mast cell (MC) disorders since these may affect the risk and severity of future sting reactions and the long-term effectiveness of VIT.
Methods
1319 individuals with Hymenoptera venom allergy (HVA) who needed VIT from referral centers in Slovenia, Austria, Croatia, and Poland underwent examination for KIT p.D816V in peripheral blood leukocytes (PBL) using a highly sensitive PCR test and tryptase genotyping by digital droplet PCR. We also included 183 control individuals with large local reactions (LLRs) to Hymenoptera stings and with asymptomatic sensitization to Hymenoptera venoms.
Results
285 of 1319 individuals recommended for VIT (21.6%) were positive for KIT p.D816V in PBL, preferably those who present with severe reaction (33.9% [n = 207 of 610] with Ring-Messmer grade 3–4 vs. 11% [n = 78 of 709] with Grade 1–2; p < .0001), whereas only 1.3% (n = 2 of 152) of controls with LLR and none with asymptomatic sensitization (n = 31) had KIT p.D816V. KIT p.D816V allelic burden was higher in those with severe reaction (median 0.018% [n = 207] in Grade 3–4 vs. 0.001% [n = 78] in Grade 1–2; p < .0001), and the majority had normal baseline serum tryptase levels (69% [n = 196 of 285]). All KIT p.D816V-positive individuals (n = 41) who underwent bone marrow (BM) biopsy were found to have underlying clonal diseases, principally BM mastocytosis. HαT was also associated with severe HVA and symptoms (p < .01), and remarkably, 31.0% (n = 31 of 100) were found to have concomitant KIT p.D816V. Concomitant HαT and KIT p.D816V showed an additive effect, and having both was associated with the highest risk for severe HVA, even higher than having either HαT or KIT p.D816V alone (OR = 3.8; p < .01).
Conclusions
By employing prospective universal tryptase genotyping and examination for KIT p.D816V in PBL in large HVA populations, we have demonstrated a high burden of clonal MC disorders and HαT in patients who require VIT.
Ključne besede: anaphylaxis, hereditary α-tryptasemia, hypersensitivity, immunotherapy, mast cell, mastocytosis, venom
Objavljeno v DiRROS: 17.06.2024; Ogledov: 1469; Prenosov: 903
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