GNB1 encephalopathy is a severe neurodevelopmental disorder caused by mutations in GNB1, which encodes the Gβ1 subunit of heterotrimeric G proteins. Using the Gnb1LacZ/+ mouse, we demonstrate that Gβ1 haploinsufficiency selectively causes cognitive deficits without affecting emotional behaviors. These functional impairments are associated with widespread reductions in dendritic spines across distinct cortical layers and dendritic compartments, indicating compromised synaptic plasticity. Multi-omics analyses further reveal concurrent metabolic alterations: transcriptomics shows upregulation of gene sets associated with mitochondrial electron transport chain and oxidative phosphorylation, while metabolomics identifies augmented glycerophospholipid catabolism in the brain and elevated systemic ketogenesis. These metabolic and synaptic phenotypes co-occur in the same model, suggesting a potential metabolic contribution to synaptic integrity that warrants direct mechanistic investigation in future studies. Collectively, our findings provide a comprehensive phenotypic and multi-omics characterization of GNB1 haploinsufficiency and highlight energy metabolism as a candidate therapeutic target, such as ketogenic diets or mitochondrial modulators, to ameliorate cognitive deficits in GNB1 encephalopathy.
Osteogenesis imperfecta (OI) in adults is associated with increased fracture risk and extra-skeletal complications. Clinical assessment and management of adults living with severe OI is complicated by the fact that the disease is rare; involvement of both musculoskeletal and extra-musculoskeletal systems; challenges associated with paediatric-to-adult transition and rarely, misdiagnosis of other bone disorders with similar clinical presentation, such as hypophosphatasia. Management of patients with severe OI (usually Sillence type III and IV) requires continuous inter-specialty collaboration and frequent regional specialist input, placing significant burdens on both clinicians and patients. The aim of this best practice guidance is to inform patients, their families, carers, generalist and specialist health professionals, and multidisciplinary clinical teams in the NHS, regarding the best practice of care for adults living with severe OI. A multi-disciplinary working group of clinicians, researchers, and patient advocates developed UK-best clinical practice guidelines for the diagnosis and management of adults with severe OI using a consensus-based approach. Given the lack of robust evidence to inform current care, these guidelines were written based on a review of the current literature, clinical expertise of the authors who have extensive experience managing patients with severe OI, and ongoing input from patients with lived experience. The guideline is divided into (1) Diagnosis – radiology, laboratory and genetic investigations; (2) Assessment – general wellbeing, musculoskeletal (fracture history, falls, mobility, pain, spine, physiotherapy and occupational therapist), extra-skeletal (dental, hearing, ophthalmic, cardiovascular, respiratory, gastrointestinal, mental health, women’s health) and radiological assessment considerations; (3) Management – multidisciplinary coordination, transition, condition awareness, lifestyle, bone strength, physiotherapy and occupational therapy, pain, orthopaedic, scoliosis, dental, hearing, mental health, women’s health general and specific measures, and monitoring. Checklists for clinicians and individuals with severe OI were developed based on the recommendations. These guidelines should inform benchmarking of care for adults with severe OI and the development of new services, improvement of existing services, as well as highlighting service gaps for clinical and research communities. Not applicable.
Hiccups lasting more than one month (“chronic singultus”) is a rare disease that impairs quality of life. Its low prevalence hampers evidence generation. The new Heidelberg Registry of Chronic Singultus (HeReChroS) aims to gather epidemiological data, assess disease burden, identify care gaps, improve treatment, and contribute to a more precise clinical characterization of the disease. This analysis of real-world data seeks to characterize the current HeReChroS patient cohort. The routinely collected data of patients with chronic singultus (ICD 10: G25.3) from October 2022 to March 2025 were retrospectively entered into HeReChroS. Descriptive statistics were calculated on data of the initial visit, including demographics, medical history, and patient-reported outcomes (PROs) such as disease burden and well-being. A total of 131 patients were included (104 male, 27 female). Common symptoms alongside hiccups included fatigue (90
Maturity-onset diabetes of the young (MODY) is the most common form of monogenic diabetes, with genetic and clinical heterogeneity emerging as significant challenges. Despite growing scholarly attention to MODY research, the overall knowledge structure, research priorities, and developmental trends in this field have not yet been systematically integrated. To ensure comprehensive coverage and compatibility with bibliometric analysis tools, relevant publications on MODY were retrieved from the Web of Science Core Collection (WoSCC) database from 2006 to 2025. Employing bibliometric methods and tools such as CiteSpace, VOSviewer, Scimago Graphica, and Microsoft Excel, we conducted visual analyses of publication trends, country and regional collaboration, institutional distribution, author contributions, co-cited journals, co-cited references, and keywords. From 2006 to 2025, a total of 1,610 publications related to MODY were identified, showing an overall increasing trend over time. The United States of America (USA), the United Kingdom (UK), and China were the major contributors to this field, with close collaborative relationships, particularly between the USA and the UK. The leading contributors by country, institution, and author were the USA (391 publications), the University of Exeter (105 publications), and Sian Ellard and Andrew T. Hattersley (50 publications each). High-frequency keywords included “gene”, “monogenic diabetes”, “children”, “prevalence”, “glucokinase”, and “mutation”. In the co-citation analysis, the study by Shields BM published in 2010 showed the highest citation frequency. These findings indicate that MODY research has primarily centered on genetic mechanisms, clinical diagnosis, and precision management, with recent attention gradually moving toward functional genomics and individualized therapeutic strategies. MODY research has evolved into a multidisciplinary field that bridges biological mechanisms, clinical characterization, and translational application. Future studies should broaden population coverage and translate molecular findings into more precise diagnosis and individualized management.
Rare liver diseases are associated with diagnostic delay, fragmented care, inconsistent management, and limited patient support. Patient pathways may help address these challenges by translating clinical guidance and patient priorities into practical, coordinated care processes. This manuscript presents a European template for developing patient-centred pathways for rare liver diseases within ERN RARE-LIVER. The template was developed through multidisciplinary collaboration involving hepatologists, specialist nurses, patient representatives, patient organisations, and EURORDIS, and was informed by clinical guidance, patient-journey principles, and iterative expert and patient review. The proposed framework follows four phases of the patient journey: pre-diagnosis, diagnosis, management, and long-term follow-up. It includes disease-specific sections, educational resources, frequently asked questions, and “10 key questions” to support shared decision-making. Pathways for non-cirrhotic portal vein thrombosis, polycystic liver disease, and portosinusoidal vascular disorder illustrate the practical application of the template. This European template provides a practical, adaptable framework aimed at supporting harmonised, multidisciplinary, and patient-centred care for rare liver diseases across European healthcare settings. Future work should evaluate implementation, usability, and impact on care coordination and patient experience.
Disease-modifying therapies for spinal muscular atrophy (SMA) require standardized follow-up to interpret treatment response. However, short-term changes may reflect measurement variability rather than true clinical change. We therefore assessed the test-retest reliability and relationships of routinely used outcome measures in adults with SMA using two standardized evaluations performed within a two-week interval. These assessments included motor function, upper-limb strength and dexterity, ambulatory performance, and respiratory function. Forty-four adults with SMA type 2 or 3 were included. No significant change was observed between test and retest visits. Most outcomes demonstrated excellent reproducibility, with intraclass correlation coefficients (ICC) >0.95. Measurement errors were low, with relative standard errors of measurement below 10
Hypoglycaemic brain injury is a persistent threat in the lives of children and young people (CYP) with hyperinsulinism (HI). Up to 50
This report aims to outline the complex and multifaceted framework within which the journey to European market access for a β-thalassemia gene therapy has unfolded, highlighting the clinical, ethical, economic, and regulatory challenges faced by all stakeholders involved. Focusing on betibeglogene autotemcel (Zynteglo), a gene therapy for β- thalassemia developed by the U.S. based biotech company Bluebird Bio, this paper analyzes official sources of information from the therapy developer, regulators, patients, health technology assessment bodies and payers with the aim of offering a measure of this complex operation that culminated in the therapy’s withdrawal from the European market in 2022.
Pathogenic variants in DEAF1 cause DEAF1-associated neurodevelopmental disorders (DAND) with autosomal-dominant (typically de novo) and autosomal-recessive (biallelic) presentations. We sought to characterize five unrelated children with de novo DEAF1 variants, define epilepsy phenotypes, and refine inheritance-specific genotype–phenotype architecture with developmental context. Trio-based whole-exome sequencing with Sanger confirmation was performed in five unrelated children. Missense variants were evaluated using structural modeling and in silico stability/physicochemical assessments. DEAF1 expression was examined using GTEx, the Human Protein Atlas, BrainSpan, Evo-devo mammalian organ transcriptomes, and single-cell brain organoid datasets. A systematic literature review (inception–March 2026) curated eligible cases for intersection-based UpSet analyses and system-level stacked summaries. Five unrelated children carried heterozygous de novo DEAF1 missense variants; four mapped to the SAND domain (p.Leu203Pro, p.Gly212Ser, p.Ile228Met, p.Leu272Ser) and one was N-terminal (p.Ala29Pro). p.Ala29Pro and p.Ile228Met were not recorded in ClinVar, HGMD Professional, or the reviewed literature. All five patients had intellectual disability/developmental delay with prominent expressive language impairment and motor delay/hypotonia. Epilepsy was observed in all patients, with onset ranging from 7 months to 2 years 8 months, and focal impaired consciousness seizures (FIC) predominated. EEG abnormalities were observed in 4 of the 5 patients, and all five were seizure-free on anti-seizure medications at the last follow-up. Structural modeling suggested variant-dependent perturbations, particularly among SAND-domain substitutions, but these findings remain computational predictions. Expression analyses supported brain-enriched, developmentally regulated DEAF1 expression and broad neuronal/progenitor expression in human brain organoids. A literature review identified 62 individuals from 15 studies; combined with our cohort, 67 individuals were analyzed (de novo n = 52; biallelic n = 15). De novo variants clustered within/around the SAND domain, whereas biallelic variants were more broadly distributed. UpSet and stacked-bar analyses revealed a shared neurodevelopmental core but distinct co-occurrence patterns, with autism/epilepsy shaping dominant intersections in de novo cases and microcephaly/MRI abnormalities contributing more prominently in biallelic disease. Our study refines the de novo clinical and allelic spectrum of DAND and delineates inheritance-specific genotype–phenotype architecture with developmental and cellular context.
Malignant hyperthermia (MH) is a rare, life-threatening pharmacogenetic disorder primarily associated with variants in the RYR1 gene. A significant proportion of identified RYR1 variants are classified as Variants of Uncertain Significance (VUS), posing a major challenge for clinical management and genetic counseling. We report a case of a 53-year-old male (proband) who developed fulminant MH during general anesthesia. Following clinical stabilization, whole-exome sequencing (WES) was performed. The initial analysis reported several variants of uncertain significance (VUS). Based on the compelling MH phenotype, the RYR1 gene was prioritized for further investigation. The candidate variant was validated by Sanger sequencing in the proband and his unaffected son and sister. WES revealed a heterozygous RYR1 variant, c.7108_7109delinsAAGCC (p.Gly2370delinsLysPro), initially classified as a VUS. Crucially, Sanger sequencing confirmed that this variant was absent in his unaffected son and sister, providing strong indirect evidence for a de novo origin. The proband’s clinical presentation was classic for MH: hyperthermia (39 °C), tachycardia, hypercapnia, muscle rigidity, hyperkalemia, and markedly elevated creatine kinase/myoglobin, which responded to dantrolene. Re-evaluation using ACMG/AMP guidelines identified the following key pathogenic evidence: PS4 (specific MH phenotype), supporting PS2 (probable de novo), PM2 (absent in population databases), PM4(in-frame indel), PP1(co-segregation in a micro-family), PP2(RYR1 is a known MH gene), PP3(computational evidence of deleteriousness), and PP4 (highly specific phenotype). This study is the first to report and validate the pathogenicity of the RYR1 c.7108_7109delinsAAGCC variant. By integrating a definitive clinical MH episode with familial segregation data, we successfully reclassified this VUS as Pathogenic. Our findings underscore the critical importance of phenotype-driven reassessment of VUS using the ACMG framework and provide definitive guidance for the lifelong anesthetic management of the proband and his family.
Phenylketonuria (PKU) is an inherited metabolic disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene, leading to impaired phenylalanine (Phe) metabolism. The mainstay of treatment is a strict low-Phe diet, which can be burdensome. Sapropterin dihydrochloride (Kuvan®), a synthetic form of tetrahydrobiopterin (BH4), offers a pharmacological alternative, potentially improving metabolic control and dietary flexibility. However, treatment response varies, and long-term effects remain uncertain. This systematic review and meta-analysis aimed to evaluate the long-term efficacy of Sapropterin in PKU patients, focusing on blood Phe levels, dietary Phe tolerance, and patient-related outcomes such as BMI and IQ. A comprehensive literature search was conducted in PubMed/MEDLINE and Web of Science, following PRISMA guidelines. Studies were included if they reported long-term outcomes of Sapropterin therapy in PKU, assessing Phe levels, dietary tolerance, or patient-related parameters. Meta-analyses were performed using the Wilcoxon rank sum test and forest plots. Nineteen studies met the inclusion criteria, with 85 patients providing baseline Phe data and 54 with post-treatment values. Sapropterin significantly reduced blood Phe levels, especially in classic PKU patients with high baseline levels (p = 0.025). Effects on dietary Phe tolerance were variable, and meta-analysis results were inconsistent. Limited data on BMI and IQ precluded firm conclusions on growth and neurocognition. Genotype analysis (n = 70) highlighted frequent PAH variants (e.g., p.L48S, p.R261Q), but genotype–response associations remained unclear. Sapropterin effectively lowers blood Phe levels in classic PKU, but further studies with standardized measures are needed to clarify its impact on dietary tolerance, growth, cognition, and genotype-based treatment response.
The SF1 gene encodes the splicing factor 1, a part of the splicing machinery. Recently, loss-of-function (LoF) variants in the SF1 gene have been suggested as a molecular cause of a neurodevelopmental spliceosomopathy. We report a unique familial case of a novel truncating variant in a single Czech family presenting with mild neurodevelopmental disorders (NDD) and variable congenital abnormalities. The c.1764_1776del variant in the last exon of the SF1 gene (NM_004630.4) was identified through exome sequencing in three affected family members. Functional analyses at the transcriptional level confirmed that this alteration does not trigger nonsense-mediated decay (NMD), and aberrant transcripts with premature termination codons are preserved. This study expands the spectrum of pathogenic variants involved in the development of new SF1-related spliceosomopathy and its diverse phenotypic effects. Our data emphasise the clinical benefits of comprehensive exome sequencing for uncovering new gene-disease connections.
Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a progressive, fatal multisystem disorder characterized by significant genotypic and geographic heterogeneity. Despite recent therapeutic breakthroughs, overlapping clinical features frequently lead to misdiagnosis and delayed intervention. A comprehensive narrative review of the literature was conducted to synthesize recent advancements in the epidemiology, diagnostic workflows, and therapeutic landscape of ATTRv-PN, with an emphasis on clinical translation and multidisciplinary management. The epidemiological profile of ATTRv-PN highlights region-specific variant distributions (e.g., p.Val50Met, p.Ala117Ser). The diagnostic paradigm has shifted towards prioritizing early genetic testing and minimally invasive biopsies, complemented by emerging serum biomarkers like neurofilament light chain (NfL) and advanced neuroimaging. Therapeutically, the landscape has been transformed by disease-modifying therapies (DMTs). Gene-silencing agents (siRNAs and ASOs) and TTR stabilizers have demonstrated robust efficacy in halting neuropathy progression. Furthermore, novel modalities, including amyloid-depleting monoclonal antibodies and in vivo CRISPR/Cas9 gene-editing therapies, show unprecedented promise in ongoing clinical trials. ATTRv-PN has entered an era of precision medicine. Overcoming diagnostic delays through “red-flag” recognition and routine genetic screening is imperative. Early, stage-adapted initiation of DMTs within a multidisciplinary care framework is crucial for optimizing long-term patient outcomes.
Skeletal dysplasia (SD) is a clinically and genetically heterogeneous group of bone and cartilage disorders. Given the typically heterogeneous and nonspecific clinical manifestations associated with these conditions, molecular testing is essential to achieve a definitive diagnosis. To elucidate the clinical and molecular characteristics of genetic skeletal disorders in the Guangxi region, we conducted a retrospective single-center study involving 434 families suspected of having SD who underwent molecular analysis in our department over an eight-year period. We analyzed their clinical and molecular genetic data. Among our cohort, facial dysmorphism and short stature emerged as the most prevalent clinical manifestations, followed by growth delay and motor delay. Notably, molecular diagnoses were made at a relatively late age. Our findings revealed a total of 34 chromosomal abnormalities and 265 Mendelian genetic disorders. According to the Nosology of genetic skeletal disorders: 2023 revision, 75 genes were implicated in 199 positive molecular diagnoses, while the remaining 66 positive diagnoses were attributed to 56 causal genes. The most frequently identified causal gene was FGFR3, with the p.G380R substitution being the predominant pathogenic variant. The overall diagnostic yield through whole-exome sequencing was found to be 64.9
Thalassemia is classified globally as a rare disease; however, it represents a major public health burden in many low‑ and middle‑income countries due to its high prevalence and limited access to care. In Indonesia, one of the world’s most genetically diverse populations, thalassemia traits present epidemiological characteristics more consistent with a common disease than a rare one in certain populations. However, the national molecular spectrum of alpha‑ and beta‑thalassemia, essential for carrier screening and prevention programs, is still insufficiently characterized. Hematological screening (red cell indices and HbA₂ levels) remains the gold standard, but molecular diagnostics are required for definitive diagnosis and accurate carrier identification. This study analyzed archived data from 4,779 individuals across Western Island Southeast Asia and Eastern Island Southeast Asia collected between 1995 and 2016. Thalassemia screening was based on hematological criteria including MCV, RBC morphology, and HbA2 levels assessed via CBC and HPLC. For 180 whole-genome sequenced individuals, pathogenic variants in HBA1/HBA2 and HBB genes were identified by cross-referencing ClinVar. Pathogenic variants were detected in 13.2
Cardio-facio-cutaneous syndrome type 4 (CFC4) is a rare RASopathy caused by germline mutations in the MAP2K2 gene, which encodes the MEK2 protein - a key kinase in the Ras/MAPK signaling pathway. Although the Ras/MAPK cascade has been widely studied due to its essential role in development and its implication in cancer biology, CFC4 remains one of the least characterized syndromes within the RASopathy spectrum. Pathogenic MAP2K2 variants have received limited attention in the literature so far, with most data derived from isolated case reports. This review aims to synthesize current knowledge on MAP2K2-related CFC4 with a particular emphasis on the molecular and functional consequences of mutations in this protein. We explore findings from in silico, in vitro, and translational studies, and highlight how particular mutations alter MEK2 function and Ras/MAPK signaling. Where specific data on CFC4 are lacking, insights are drawn from broader RASopathy research to suggest mechanistic parallels and potential therapeutic implications. By gathering and integrating the current knowledge on MEK2 biology, this advances our understanding of MEK2-driven pathogenesis and supports the development of more effective therapeutic strategies for individuals affected by CFC4.
Neuronopathic mucopolysaccharidosis type II (MPS II; Hunter syndrome) is characterized by progressive multisystemic impacts, including cognitive impairment and behavioral problems. The Vineland Adaptive Behavior Scales, second edition (VABS-II) is recommended for assessing adaptive behavior in MPS II clinical studies; recently, an increase in VABS-II age-equivalent scores of 3 months (3AEq) has been defined as a threshold for improvement. The aim of the present study was to gain caregiver insights on what constitutes meaningful change on the VABS-II in response to treatment for children with neuronopathic MPS II. Ten semi-structured interviews were conducted with 11 caregivers of 11 children with neuronopathic MPS II aged 3–6 years old in the UK and USA. Caregivers were presented with hypothetical vignettes detailing changes in adaptive behavior and VABS-II scores in response to treatment over 1 year and were asked to select which one(s) represented a minimal meaningful change. The scores for the selected meaningful changes were then compared with those equivalent to an increase of 3AEq to assess the adequacy of this threshold. Caregivers discussed the rationale for their choices. For all nine VABS-II categories (feeding, drinking, undressing, dressing, brushing teeth and toileting [Personal Subdomain]; sharing skills [Interpersonal Relationships Subdomain]; Play and Leisure Subdomain; and Maladaptive Behavior Domain), the hypothetical vignette most commonly selected by caregivers as representing a minimal meaningful change was associated with the smallest change. The significant impact of small increases in independence and cognitive and physical abilities to perform daily activities were highlighted. For each functional activity within the Personal Subdomain, the majority of caregivers selected vignettes associated with changes in raw scores that were below the total Personal Subdomain raw score equivalent to a change of 3AEq. For sharing skills (Interpersonal Subdomain) and for the Play and Leisure Subdomain, the majority of caregivers chose vignettes associated with raw score changes that were below or equal, respectively, to raw scores associated with a change of 3AEq. These insights from caregivers support the use of VABS-II for assessing adaptive behavior in children with neuronopathic MPS II and the use of 3AEq as a threshold for meaningful change.
Neurofibromatosis type 1 (NF1) is a rare autosomal dominant multisystem disorder caused by NF1 gene variants. Although NF1 shows marked clinical and genetic heterogeneity, large Chinese cohorts integrating clinical features, NF1 variant spectrum, and external variant contextualization remain limited. We conducted a cross-sectional study of 847 clinically confirmed Chinese patients with NF1 to characterize demographic features, clinical manifestations, DNB-defined severity, and NF1 variant spectrum. Whole-exome sequencing was performed in 211 patients. Transcript-level variant distribution was assessed using a 500-bp sliding-window approach and further contextualized using ClinVar-derived NF1 variant data. Among 847 patients, the median age was 23 years, 27.5
