IUBMB Life. 2025 Jun;77(6):e70031. doi: 10.1002/iub.70031.

ABSTRACT

Over 7000 rare diseases have been described, collectively affecting 350 million people worldwide. Most of these conditions result from nonsense mutations, representing approximately 10% of all genetic mutations associated with human inherited diseases. Nonsense mutations convert a sense codon into a premature termination codon (PTC), leading to premature translation termination and the production of truncated, nonfunctional proteins. This results in a loss-of-function phenotype in many genetic disorders, contributing to the disease's severity and progression. The molecular mechanisms of PTC formation involve various genetic alterations, including single-nucleotide changes, frameshifts, and splicing mutations. The nonsense-mediated mRNA decay (NMD) pathway degrades mRNAs containing premature termination codons (PTCs). In contrast, 25% of PTC mRNAs, depending on the PTC position and cellular context, can evade NMD, resulting in the synthesis of truncated proteins. A termination codon during translation is essential for proper protein synthesis, and translational readthrough-a process in which the ribosome bypasses the PTC and reaches the natural stop codon-may restore some level of protein function. The effectiveness of readthrough depends on the surrounding genetic context and the type of amino acid incorporated at the PTC position. This review aims to explore the molecular characteristics of nonsense-related diseases (NRDs), including cystic fibrosis, hemophilia, Fabry disease, choroideremia, Usher syndrome, Shwachman-Diamond syndrome, and certain hereditary neuropathies and cancers.

PMID:40474765 | DOI:10.1002/iub.70031

Orphanet J Rare Dis. 2025 Jun 5;20(1):277. doi: 10.1186/s13023-025-03805-1.

ABSTRACT

Rare diseases present critical challenges to healthcare systems, patients, and caregivers due to their low prevalence and unique characteristics. Designing clinical trials and developing statistical methodologies for evaluating interventions in rare diseases face several challenges. The "EBStatMax" project, part of the European Joint Programme on Rare Diseases' Demonstration Projects, aimed to address one of these challenges, namely: designing and analyzing longitudinal cross-over data in rare diseases, like Epidermolysis bullosa simplex (EBS). Although the main findings of the project have been published elsewhere, this manuscript reflects on additional hurdles encountered during the project, particularly regarding outcomes and methodological considerations. It explores issues surrounding outcome measurement, statistical methodology, and clinical considerations, emphasizing their broader relevance to methodological advancements in rare disease research beyond this specific case. This manuscript highlights the critical role of international collaboration in rare disease research to enhance evidence quality and aims to inspire further advancements in the field.

PMID:40474287 | DOI:10.1186/s13023-025-03805-1

Orphanet J Rare Dis. 2025 Jun 5;20(1):279. doi: 10.1186/s13023-025-03828-8.

ABSTRACT

Gene therapy has transitioned from a long-awaited promise to a clinical reality, offering transformative treatments for rare congenital diseases and certain cancers, which have a significant impact on patients' lives. Current approaches focus on gene replacement therapy, either in vivo or ex vivo, mostly utilizing viral vectors to deliver therapeutic genes into target cells. However, refining these techniques is essential to overcome challenges and complications associated with gene therapy to ensure long-term safety and efficacy. Slovenia has witnessed significant advancements in this field since 2018, marked by successful gene therapy trials and treatments for various rare diseases. Significant strides have been made in the field of gene therapy in Slovenia, treating patients with spinal muscular atrophy and rare metabolic disorders, including the pioneering work on CTNNB1 syndrome. Additionally, immune gene therapy, exemplified by IL-12 adjuvant therapy for cancer, has been a focus of research in Slovenia. Through patient-centred initiatives and international collaborations, researchers in Slovenia are advancing preclinical research and clinical trials, paving the way for accessible gene therapies. Establishing clinical infrastructure and genomic diagnostics for rare diseases is crucial for gene therapy implementation. Efforts in this regard in Slovenia, including the establishment of a Centre for Rare Diseases, Centre for the Technologies of Gene and Cell Therapy, and rapid genomic diagnostics, demonstrate a commitment to comprehensive patient care. Despite the promises of gene therapy, challenges remain, including cost, distribution, efficacy, and long-term safety. Collaborative efforts are essential to address these challenges and ensure equitable access to innovative therapies for patients with rare diseases.

PMID:40474241 | DOI:10.1186/s13023-025-03828-8

Orphanet J Rare Dis. 2025 Jun 5;20(1):280. doi: 10.1186/s13023-025-03762-9.

ABSTRACT

BACKGROUND: Duchenne muscular dystrophy (DMD) is a progressive genetic disease that leads to degeneration of muscles, including respiratory muscles, and requires early introduction of non-invasive ventilation (NIV). Parental knowledge and management strategies for pulmonary care are essential when respiratory function is compromised, particularly in conditions involving sleep apnea and the progression of chronic respiratory failure. The aim of this study was to assess parental knowledge of key aspects of pulmonary care in DMD and to identify knowledge gaps that may influence therapeutic decisions.

METHODS: A cross-sectional survey was conducted as part of the multidisciplinary care program for DMD at the Center for Rare Diseases in Gdańsk, accredited by the World Duchenne Organization. The questionnaire assessed (1) demographic and clinical details, (2) pulmonary healthcare practices, (3) understanding of pulmonary rehabilitation, (4) knowledge about NIV, and (5) sources of information on respiratory care.

RESULTS: The study included 111 parents (F/M 83/28, mean age 45.5 ± 6.75 years) of 111 children with DMD (all male, mean age 11.5 ± 5.45 years; 38% non-ambulatory). The majority of individuals (77.5%) regularly visited a pulmonary specialist with spirometry performed. Most parents reported satisfactory knowledge about respiratory issues in DMD but 77% of them reported insufficient knowledge about NIV (Chi2 = 53.4, df = 12, p = 0.00). Only 11% weren't afraid to use NIV in the future, while 73% were afraid because of a lack of or inaccurate information. Physicians were the primary source of knowledge for pulmonary care, while the internet and peer experiences were rarely used.

CONCLUSION: The majority of parents of children with DMD understand the basics of pulmonary problems. A significant information gap exists concerning advanced respiratory interventions such as non-invasive ventilation (NIV). This leads to anxiety among parents and impairs therapeutic decision-making, delaying appropriate treatment including respiratory support. There is a need for respiratory education programmes for parents and patients, especially as the estimated longer survival time for patients with DMD will make respiratory challenges even more significant.

PMID:40474208 | DOI:10.1186/s13023-025-03762-9

BMC Health Serv Res. 2025 Jun 4;25(1):799. doi: 10.1186/s12913-025-12784-9.

ABSTRACT

BACKGROUND AND METHODS: The organization of care profoundly impacts the variability in the quality of care provided to patients and the equity of access to care. The lack of coordination of care, of communication among healthcare providers, healthcare professionals, and patients, and the duplication of services provided to the patients represent some paradigmatic examples of organizational barriers to deliver high-quality patient-centered care and to promote equitable access to healthcare services. Patient care pathways (PCPs) are valuable tools for the (re)design and the (re)definition of the provision of healthcare services to patients. This work represents the first application of the RarERN Path© methodology for the (re)design of Patient Care Pathways (PCPs) to Ataxias, Dystonia, and Phenylketonuria (PKU). The study was conducted with the support of Academic Partners and in collaboration with experts from two of the 24 European Reference Networks for rare diseases (ERN RND and MetabERN).

RESULTS: The application of some of the phases of RarERN Path© methodology enabled the translation of the good practices already in place in the centers of expertise into a common optimized PCP, one for each of the three diseases, integrating the expertise of some reference centers of excellence with the patients' perspectives, and principally focusing on the organization of care.

CONCLUSIONS: The PCPs proposed for progressive ataxias, dystonia, and PKU provide insight into the value of specialized centers in diagnosing and managing patients with rare and complex conditions and are the results of a co-designed optimized process integrating the good practices of the centers of excellence and expertise with the perspectives of the patients' representatives. This integrated approach allowed for the re-design and optimization of the organizational dimensions of the patient's care pathways.

PMID:40468287 | DOI:10.1186/s12913-025-12784-9

Sci Transl Med. 2025 Jun 4;17(801):eadq1810. doi: 10.1126/scitranslmed.adq1810. Epub 2025 Jun 4.

ABSTRACT

Hydrocephalus (HC) is a failure of brain and cerebrospinal fluid (CSF) homeostasis often associated with dilation of the CSF-filled ventricles (ventriculomegaly). Hallmarks of HC include aberrant CSF dynamics, neural stem cell dysfunction resulting in impaired neurogenesis and corticogenesis, biomechanical instability at the brain-CSF interface, and disrupted synaptogenesis and neural circuitry. Pleiotropic mechanisms, including genetic and environmental insults to the brain, contribute to neurodevelopmental comorbidities. Hypothesis generation from genome-wide, single-cell multi-omic analyses coupled to experimental validation using induced pluripotent stem cell-derived cerebral organoids will refine molecular classification of HC subtypes and may lead to precision-based surgical and pharmacologic treatments.

PMID:40465691 | DOI:10.1126/scitranslmed.adq1810

Orphanet J Rare Dis. 2025 Jun 2;20(1):266. doi: 10.1186/s13023-025-03756-7.

ABSTRACT

BACKGROUND: In the European Union (EU), the orphan legislation, aiming to increase the number of pharmacotherapies available for rare diseases, came into force in April 2000. This study examined the development of the selection of orphan medicines granted marketing authorisation, their approved indications, and the number of orphan medicines developed for paediatric use in EU during 2000-2022. This study also examined the availability of the orphan medicines with a marketing authorisation in the Finnish market in order to demonstrate their country level uptake in a single member state.

METHODS: The material on orphan medicines' marketing authorisations and their introduction were collected from the European Commission's Community Registers in June 2022 and analysed with a qualitative document analysis. This study covered the period 2000-2022 since the introduction of the orphan legislation, and comparisons were made in 10-year periods of, 2001-2010 and 2011-2020.

RESULTS: By May 2022, there were 213 novel orphan medicines approved in Europe during the observation period. Of them, 67% (n = 142) were on the market in Finland in May 2024. The number of new orphan medicines approved in Europe doubled from 63 products in 2001-2010 to 127 products in 2011-2020. Several orphan medicines were developed for certain type of rare diseases, such as haematological cancers. The proportion of orphan medicines approved for paediatric use decreased from 55% in 2001-2010 to 42% in 2011-2020.

CONCLUSION: The number of orphan medicines available within EU increased significantly after the orphan legislation came into force. The development of orphan medicines seemed to often focus on diseases or disease groups that already have available treatment options, while several rare diseases remain without available treatment. Even though rare diseases are more common in children, orphan medicines have not been developed for paediatric use in the same proportion.

PMID:40457478 | DOI:10.1186/s13023-025-03756-7

PLoS One. 2025 Jun 2;20(6):e0321864. doi: 10.1371/journal.pone.0321864. eCollection 2025.

ABSTRACT

Factor V deficiency is a congenital coagulation disorder characterized by the absence or malfunction of factor V (FV). The purpose of this study was to develop a viable FV-deficient mouse model using CRISPR/Cas9 technology. A viable pathological model of the disease was not available to develop new therapies. A previous in silico study was performed to select a mutation causing a mild disease phenotype in humans (Thr1898Met missense). Such mutation was replicated in mice by CRISPR-mediated homology directed repair. Following crossing, homozygous individuals were subjected to coagulometry assays, including FV levels, prothrombin time (PT), and activated partial thromboplastin time (aPTT). The in silico study suggested that the mutation destabilizes FV structure of both mouse and human variants, putatively producing a mild phenotype of the disease in mice. Mendelian inheritance was observed in the offspring. No spontaneous signs of blood clotting disturbances, premature deaths or gestational dysfunctions were observed. FV levels in homozygous animals were 24.5% ± 5.1; 39.7 sec ± 2.8; PT was 61.8% ± 6.3; 23.4 sec ± 1.6 (INR = 1.47 ± 0.12); and aPTT was 46.9 sec ± 3.2. A viable FV-deficient mouse model was generated by introducing a missense mutation in FV. The model exhibits a mild phenotype of the disease, akin to that observed in humans.

PMID:40455764 | DOI:10.1371/journal.pone.0321864

Depress Anxiety. 2025 May 22;2025:9002779. doi: 10.1155/da/9002779. eCollection 2025.

ABSTRACT

Background: People living with a rare disease are a vulnerable patient group and experience challenges in participation and healthcare. Due to changes in healthcare and threat of the infection during coronavirus disease 2019 (COVID-19) pandemic, people living with rare diseases have been particularly affected. Therefore, this study aimed to investigate depressive symptoms and symptoms of anxiety during the COVID-19 pandemic and identify factors associated with symptom levels. Methods: One-hundred and seventy-two people living with a rare disease were recruited from centers for rare diseases and patient organizations in Germany from January 2021 to January 2022. In addition to descriptive analyses and group comparisons, we applied multiple linear regression models to identify factors associated with outcome variables of interest (depressive and anxiety symptoms, assessed by the Hospital Anxiety and Depression Scale [HADS]). Results: For the depressive symptoms, 14% of the participants reached the cutoff for moderate and 14.5% for a high level of depressive symptoms. Concerning anxiety symptoms, 22% reported moderate levels of anxiety and 13.4% reported high levels of anxiety. Higher depressive symptoms were significantly associated with older age, lower socioeconomic status, having severe or varying symptoms compared to low symptom severity, lower treatment satisfaction, lower social support, and more unmet needs. Higher anxiety levels were associated with more unmet needs and more intense COVID-19-related concerns. Conclusions: The findings indicate red flags of high symptoms that should be considered during routine care of patients with rare diseases. Healthcare providers should be sensitized for the need for psychosocial support and use a quick assessment to assign patients in need to specific support programs. Trial Registration: German Clinical Trials Registry: DRKS00020488.

PMID:40444181 | PMC:PMC12122157 | DOI:10.1155/da/9002779

PLoS One. 2025 May 29;20(5):e0323043. doi: 10.1371/journal.pone.0323043. eCollection 2025.

ABSTRACT

OBJECTIVE: Isolated sulfite oxidase deficiency (ISOD; OMIM #272300) is a devastating rare neurometabolic disorder due to biallelic pathogenic variants in the SUOX gene, that typically results in neonatal refractory epilepsy and progressive severe encephalopathy. Knowledge on the quantitative natural history of ISOD is limited and clinical outcome parameters for future clinical trials remain to be defined.

MATERIAL AND METHODS: We performed a comprehensive analysis of published cases (N=74) with ISOD applying quantitative retrospective natural history modeling (QUARNAM). Main outcome parameters were age of disease onset, diagnostic delay and survival. Clinical characteristics and potential associations between biochemical parameters and clinical outcome (i.e. age of disease onset, survival) were explored.

RESULTS: The median survival period of the study cohort was 60 months. ISOD typically presented shortly after birth with a median age of onset of 3 days. Median age at diagnosis was 10 months, leading to a substantial median diagnostic delay of 5.7 months. Homocysteine concentrations in plasma correlated with age of disease onset. An association of biochemical parameters of cysteine metabolism and survival could not be identified.

CONCLUSION: The present analysis describes long-term outcome measures adding to the quantitative understanding of the natural history of ISOD, which might be helpful in the planning of prospective clinical trials and potentially stimulate development of targeted therapies in the future.

PMID:40440599 | DOI:10.1371/journal.pone.0323043

Medicina (Kaunas). 2025 May 12;61(5):881. doi: 10.3390/medicina61050881.

ABSTRACT

Background and Objectives: Poretti-Boltshauser syndrome (PBS) is a rare, autosomal recessive disorder caused by pathogenic variants in the LAMA1 gene, resulting in laminin dysfunction. This manifests as a cerebellar malformation with cysts, and patients present with developmental delay and ataxia; however, ocular features are not well-characterised. We aimed to summarise the ocular phenotypes of PBS based on cases reported in the literature. Materials and Methods: A literature search was conducted on Medline, Embase, and PubMed on PBS and its ocular associations. Genetically confirmed PBS cases were reviewed, and genotype-phenotype correlations were investigated. Results: Comprehensive reporting of genotypes and associated systemic and ocular phenotypes was available in 51 patients with PBS, who had 52 distinct variants in LAMA1. Most patients carried homozygous variants. The most common genotype was a c.2935delA homozygous mutation, followed by the c.768+1G>A; c.6701delC compound heterozygous mutation. High myopia was the most common ocular phenotype (n = 39), followed by strabismus (n = 27) and ocular motor apraxia (n = 26). A wide range of other ocular manifestations, including retinal dystrophy, retinal neovascularisation, retinal detachment, strabismus, nystagmus, optic disc and iris hypoplasia, were reported. Patients with the same genotype exhibited variable expressivity. Conclusions: PBS has a broad ocular phenotypic spectrum, and characterisation of this variability is important for making an accurate diagnosis and informing genetic counselling.

PMID:40428839 | PMC:PMC12113114 | DOI:10.3390/medicina61050881

Orphanet J Rare Dis. 2025 May 28;20(1):258. doi: 10.1186/s13023-025-03754-9.

ABSTRACT

INTRODUCTION: In Thailand, obtaining medicines for rare diseases presents significant challenges, with limited evidence highlighting these issues.

OBJECTIVES: To evaluate the accessibility of medicines and the extent of health insurance coverage for treatments of rare diseases in Thailand.

METHOD: This study utilized a thorough review of current health policies, drug registration database, and insurance coverage conditions. Additionally, procurement data from the Ministry of Finance was analyzed to verify the acquisition of medicines intended for the treatment of rare diseases.

RESULTS: A review of the availability and procurement of medicines for rare diseases in Thailand revealed considerable limitations in both registration and accessibility. According to the International Rare Diseases Research Consortium, only 46.80% of their recommended medicines were registered in Thailand, and of these, just 22.93% were included in the national essential medicines list. Additionally, a review of the state's pharmaceutical procurement dataset over the past 5 years showed that merely 31.70% of these registered drugs had been purchased from suppliers for use in hospitals.

CONCLUSION: To address these issues, the study recommended accelerating the approval process for rare disease medicines, expanding health insurance coverage, establishing financial support for patients, and creating a specific pricing policy for orphan drugs. Collaborative efforts among stakeholders were emphasized as crucial for improving access to essential medicines and enhancing treatment outcomes for patients with rare diseases in Thailand.

PMID:40437602 | DOI:10.1186/s13023-025-03754-9

Genes (Basel). 2025 Apr 29;16(5):522. doi: 10.3390/genes16050522.

ABSTRACT

BACKGROUND/OBJECTIVES: Genodermatoses are genetic conditions with clinical symptoms manifesting in the skin and adjoining tissues, individually rare but comprising a large and heterogeneous group of disorders that represents 15% of genetic diseases. This article discusses the results of individuals with genodermatoses from a reference center for rare diseases studied through whole genome sequencing conducted by the Brazilian Rare Genomes Project between 2021 and 2023.

METHODS: A retrospective case series with data comprising sex, age at first assessment in the hospital, family history, clinical findings, and molecular results.

RESULTS: Excluding neurofibromatosis type 1, Ehlers-Danlos syndrome and RASopathies are discussed elsewhere. Diagnoses in this work comprised ectodermal dysplasias (n = 6), ichthyosis (n = 4), albinism (n = 4), tuberous sclerosis complex (n = 4), and incontinentia pigmenti (n = 3), in addition to 11 others with individual rare conditions. The sex ratio was 17:16 (M:F), consanguinity was present in 6/33 (18%), and the age at the first evaluation ranged from neonatal to 26 years (median 13.65 years). Negative results were 3/33 (9%), novel variants were 17/41 (41.4%), and 7/30 (23%) presented initially with a double molecular diagnosis, three confirming composed phenotypes.

CONCLUSIONS: Besides reporting 17 novel variants in 14 genes (BLM, CACNA1B, EDA, ELN, ENG, ERC6, EVC2, PNPLA1, PITCH1, PORCN, SIN3A, TP63, TYR, and WNT10B), the study also identified three atypical clinical presentations due to dual diagnoses, and the c.454C>T variant in the SDR9C7 gene, previously reported only in dogs, was, for the first time, confirmed as causative for ichthyosis in humans.

PMID:40428344 | DOI:10.3390/genes16050522

Genes (Basel). 2025 Apr 25;16(5):490. doi: 10.3390/genes16050490.

ABSTRACT

Background: Dyggve-Melchior-Clausen syndrome (DMC) is a rare autosomal recessive skeletal dysplasia characterized by dwarfism, coarse facial features, and intellectual disability. Caused by loss-of-function variants in the DYM gene, which encodes dymeclin, DMC is predominantly reported in consanguineous populations but remains poorly studied in South America. Methods: We report a 21-year-old Ecuadorian male with clinical features suggestive of DMC. Comprehensive clinical, radiological, and genetic evaluations were conducted, including clinical exome sequencing and Sanger sequencing, followed by an in silico analysis to assess the structural and functional consequences of the identified variant. Results: Exome sequencing identified a homozygous c.1878delA (p.Lys626fs) frameshift variant in the DYM gene, which was confirmed by Sanger sequencing as inherited from heterozygous parents. Variants of uncertain significance were detected in other skeletal dysplasia-related genes but did not correlate with the phenotype. A comprehensive review of reported DYM variants was also conducted. Conclusions: This report documents the first case of DMC in Ecuador and the second in South America, expanding the global understanding of DMC's genetic diversity. It underscores the value of next-generation sequencing in rare disease diagnostics and highlights the critical need for inclusive genomic research in underrepresented populations to improve the understanding of genetic heterogeneity and rare disease epidemiology.

PMID:40428312 | DOI:10.3390/genes16050490

Orphanet J Rare Dis. 2025 May 27;20(1):256. doi: 10.1186/s13023-025-03740-1.

ABSTRACT

Mechanistic target of rapamycin (mTOR) is a highly conserved serine/threonine kinase that regulates key cellular processes including cell growth, autophagy and metabolism. Hyperactivation of the mTOR pathway causes a group of rare and ultrarare genetic diseases. mTOR pathway diseases have diverse clinical manifestations that are managed by distinct medical disciplines but share a common underlying molecular basis. There is a now a deep understanding of the molecular underpinning that regulates the mTOR pathway but effective treatments for most mTOR pathway diseases are lacking. Translating scientific knowledge into clinical applications to benefit the unmet clinical needs of patients is a major challenge common to many rare diseases. In this article we expound how mTOR pathway diseases provide an opportunity to coordinate basic and translational disease research across the group, together with industry, medical research foundations, charities and patient groups, by pooling expertise and driving progress to benefit patients. We outline the germline and somatic mutations in the mTOR pathway that cause rare diseases and summarise the prevalence, genetic basis, clinical manifestations, pathophysiology and current treatments for each disease in this group. We describe the challenges and opportunities for progress in elucidating the underlying mechanisms, improving diagnosis and prognosis, as well as the development and approval of new therapies for mTOR pathway diseases. We illustrate the crucial role of patient public involvement and engagement in rare disease and mTOR pathway disease research. Finally, we explain how the mTOR Pathway Diseases node, part of the Research Disease Research UK Platform, will address these challenges to improve the understanding, diagnosis and treatment of mTOR pathway diseases.

PMID:40426219 | DOI:10.1186/s13023-025-03740-1

Infection. 2025 May 27. doi: 10.1007/s15010-025-02559-z. Online ahead of print.

ABSTRACT

Hemophagocytic lymphohistiocytosis (HLH) is an orphan disease characterized by excessive inflammation and poor outcome. We sought to further characterize clinical features, courses, and risk factors of secondary HLH (sHLH) triggered by infection (iHLH). 28 (43.1%) of 65 adult sHLH cases treated at our hospital from 2012-2024 were infection-associated. iHLH patients were mostly male (71.4%). Infectious agents most frequently detected were EBV (57.1%) and leishmania (14.3%). The median time to diagnosis was 13 [6.0;24.8] days. iHLH patients had a mortality rate of 39.3% (median follow-up time: 735 [336;1140] days), worse survival than patients with autoimmune-triggered (hazard ratio: 3.33 (1.01-11.10), p = 0.049), and better survival than patients with paraneoplastic HLH (hazard ratio: 0.19 (0.10-0.84), p = 0.002). Elevated levels of soluble interleukin-2 receptor (sIL2R; > 6,000 I/U), low thrombocyte counts (< 40 G/l), and a history of malignant disease were associated with adverse outcomes. Protracted time to diagnosis was associated with severe disease courses and with leishmaniosis. Further, sIL2R levels correlated positively with prolonged aPTT and thrombocytopenia, and hypertriglyceridemia with elevated INRs. Patients with an elevated sIL2R:ferritin ratio were more likely to have a history of malignant comorbidities. Taken together, sIL2R, thrombocytopenia, and a history of malignant disease are important prognostic factors of iHLH. Patients with high sIL2R levels or hypertriglyceridemia may be at higher risk of bleeding, and patients with elevated sIL2R:ferritin ratios should be assessed for possible malignant comorbidities. Lastly, increased awareness of the disease and newly emerging pathogens (i.e. leishmania) may shorten the time to diagnosis, and thus reduce severe courses of iHLH.

PMID:40425997 | DOI:10.1007/s15010-025-02559-z

Hum Mol Genet. 2025 May 27:ddaf082. doi: 10.1093/hmg/ddaf082. Online ahead of print.

ABSTRACT

Rare variants affecting the epigenetic regulator KDM2B cause a recently delineated neurodevelopmental disorder. Interestingly, we previously identified both a general KDM2B-associated episignature and a subsignature specific to variants in the DNA-binding CxxC domain. In light of the existence of a distinct subsignature, we set out to determine if KDM2B CxxC variants are associated with a unique phenotype and disease mechanism. We recruited individuals with heterozygous CxxC variants and assessed the variants' effect on protein expression and DNA-binding ability. We analyzed clinical data from 19 individuals, including ten previously undescribed individuals with seven novel CxxC variants. The core phenotype of the KDM2B-CxxC cohort is more extensive as compared to that of individuals with KDM2B haploinsufficiency. All individuals with CxxC variants presented with developmental delay, mainly in the speech and motor domain, in addition to variable intellectual disability and mild facial dysmorphism. Congenital heart defects were observed in up to 78% of individuals, with additional common findings including musculoskeletal, ophthalmological, and urogenital anomalies, as well as behavioral challenges and feeding difficulties. Functional assays revealed that while mutant KDM2B protein with CxxC variants can be expressed in vitro, its DNA-binding ability is significantly reduced compared to wildtype. This study shows that KDM2B CxxC variants cause a distinct neurodevelopmental syndrome, possibly through a molecular mechanism different from haploinsufficiency.

PMID:40420380 | DOI:10.1093/hmg/ddaf082

Genome Med. 2025 May 26;17(1):61. doi: 10.1186/s13073-025-01491-z.

ABSTRACT

Many people with rare diseases cannot access personalized therapies because they do not have a confirmed genetic diagnosis. Promising technologies including proteomics are underutilized in routine diagnostic practice. It is time to incorporate proteomics into the diagnostic workflow to shorten time to diagnosis and expand treatment options for rare disease.

PMID:40420250 | DOI:10.1186/s13073-025-01491-z

J Transl Med. 2025 May 26;23(1):586. doi: 10.1186/s12967-025-06609-w.

ABSTRACT

BACKGROUND: Approximately 60% of rare disease cases remain unsolved after exome and genome sequencing (ES/GS). Blood RNA sequencing (RNA-seq) complements DNA-level diagnosis by revealing the functional impact of variants on gene expression and splicing, but to what extent RNA-driven approaches offer diagnostic benefits across different scenarios-with and without pre-existing candidate variants-remains uncertain.

METHODS: 128 unrelated probands with suspected Mendelian disorders who had previously undergone ES/GS were recruited. A validation cohort (n = 7, with variants expected to alter RNA) and a test cohort (n = 121, including 10 with variants of uncertain significance (VUS) and 111 with no previously identified candidate variants) were analyzed. Blood RNA-seq was performed, and aberrant splicing (AS) and aberrant expression (AE) were detected using the DROP pipeline. SpliceAI predictions were compared with RNA-seq results for splicing-related VUS variants, and pathogenicity was re-evaluated. AS/AE outliers were evaluated for diagnostic potential in cases without candidate variants. The feasibility of an RNA-driven approach was assessed by ranking causal variant-associated aberrant events.

RESULTS: The pipeline correctly identified all expected AS/AE events in the validation cohort. In the test cohort with candidate VUS, RNA-seq provided a 60% (6/10) diagnostic uplift. Notably, SpliceAI predictions matched RNA-seq observations perfectly only in 40% of these VUS. A 2.7% (3/111) diagnostic uplift was achieved in the test cohort with no prior candidates. Overall, target AS and AE events ranked among the top eight in 14 of the 16 diagnosed cases using a purely RNA-driven approach; however, two cases would have been missed without prior candidate identification from DNA sequencing.

CONCLUSION: Blood RNA-seq is highly effective in refining the interpretation of splicing VUS, frequently leading to reclassification and diagnosis. Meanwhile, RNA-driven identification of causal variants shows a more modest yield in cases without prior candidates. This study supports an RNA-complementary approach as the preferred strategy for clinical utility.

PMID:40420094 | DOI:10.1186/s12967-025-06609-w

JMIR Infodemiology. 2025 May 26;5:e69040. doi: 10.2196/69040.

ABSTRACT

BACKGROUND: Eosinophilia and hypereosinophilic syndrome (HES) are rare disorders grouped under the term hypereosinophilic disorders. They are diagnosed based on an increased number of eosinophils. They can also cause serious symptoms, including skin, lung, and gastrointestinal problems. These disorders are very rarely recognized due to their rarity and misdiagnosis.

OBJECTIVE: This study analyzes public interest in hypereosinophilic disorders using data on internet search volume in Germany between 2020 and 2023. Objectives include identifying frequently searched terms, evaluating temporal trends, analyzing seasonal patterns, evaluating geographic differences in search behavior, and identifying unmet information needs and frequently searched risk factors.

METHODS: A retrospective analysis using Google Ads Keyword Planner gathered monthly search volume data for 12 German terms related to hypereosinophilic disorders. These terms were selected based on their medical relevance and common usage identified from medical literature. Data were analyzed descriptively, with trends, seasonal variations, and geographical distributions examined. Chi-square tests and correlation analysis assessed statistical significance.

RESULTS: A total of 178 keywords were identified, resulting in a search volume of 1,745,540 queries. The top keyword was "eosophile," a misspelling, followed by "eosinophilia" and "HES." The main categories included "Eosinophilia," "Eosinophils," and "Churg-Strauss syndrome." Temporal analysis showed seasonal growth in search volumes, peaking in January 2023, with higher interest during winter. Geographical analysis showed regional variations.

CONCLUSIONS: This research shows a growing public interest in eosinophilic diseases, reflected by a steadily increasing search volume over time. This is particularly evident in searches for basic definitions and diagnostic criteria, such as "eosinophils" or "symptoms of eosinophilic diseases." This increase in search volume, which peaked in January 2023, indicates an increased interest in accurate and readily available information for rare conditions.

PMID:40418815 | DOI:10.2196/69040