BACKGROUND:Fibromuscular dysplasia (FMD) is a non-atherosclerotic vascular disease that predominantly affects renal and cerebral vessels, causing renovascular hypertension and stroke. Because FMD occurs extremely rarely in early childhood, the clinical presentation at onset and the long-term outcome of childhood-onset FMD remain to be clarified. CLINICAL PRESENTATION:A 19-month-old boy presented with moyamoya syndrome, presenting with recurrent ischemic attacks and hemi-convulsive seizures. Systolic blood pressure exceeded 200 mmHg on admission, and abdominal CT angiography revealed bilateral stenosis of the renal arteries with a "string-of-beads" appearance. Intensive care with continuous thiamylal infusion was required to manage recurrent seizures. On Day 34 of admission, a left nephrectomy was performed to control his blood pressure. Pathological analysis revealed medial fibromuscular dysplasia and intimal thickening of the renal artery, confirming FMD. At age 2 years and 3 months, he developed nonconvulsive status epilepticus. After recovery, he showed severe spastic quadriplegia and cognitive decline. Neuroimaging studies revealed rapid cerebral atrophy over an 11-month period of observation. RESULTS:Exome sequencing for arteriopathy-related genes excluded pathogenic variants or copy number variants spanning FMD-related loci. Cytokine analyses showed an elevated TGF-β1 level in cerebrospinal fluid (125 pg/mL) in comparison with those of controls (n = 5; range 6.8-56.1 pg/mL). CONCLUSIONS:This patient highlights the severe clinical presentation and the rapid deterioration of motor and cognitive functions in an early-onset form of FMD. Childhood-onset FMD might be related to unfavorable outcomes of brain functions due to systemic vasculopathy.
BACKGROUND:Rare disease care pathways are complex and require coordination among specialised and non-specialised services, including genetic diagnostics, multidisciplinary expertise, and cross-border collaboration. Despite increasing policy attention and the establishment of European Reference Networks, the development and implementation of cohesive rare disease care pathways remain inconsistent across Europe. A shared, consensus-based framework reflecting stakeholder priorities is needed. METHODS:This exploratory study combined structured stakeholder workshops and a Delphi consensus process. Nine workshops were conducted within the JARDIN project, engaging stakeholders from 16 European countries. Data were collected using standardised Miro boards and analysed thematically using MAXQDA, guided by the SEIPS 2.0 framework. Insights from this analysis informed the development of statements, which were evaluated through a Delphi survey. Consensus was predefined as a median score of at least 4, an interquartile range (IQR) ≤1, and ≥80% agreement (ratings 4-5). RESULTS:A total of 216 individuals participated in the workshops, of whom 164 contributed during live sessions. Workshop data generated 1767 entries mapped across SEIPS domains. Seven thematic areas were identified: national strategy and governance; financing and sustainability; organisational structures and care coordination; access and equity; digital infrastructure and data systems; capacity building and education; and patient empowerment. Eighty-eight participants completed the Delphi survey, and consensus was achieved on all statements in the first round. CONCLUSION:The findings demonstrate strong cross-country agreement on system-level requirements for effective rare disease care pathways. These consensus statements provide a structured framework for developing national care pathways and integrating European Reference Networks activities into routine healthcare systems.
Integrating European Reference Networks (ERNs) into national health systems is crucial for rare disease care but remains challenging due to inconsistent support structures across countries. This study used a 2024-2025 multi-stakeholder survey of ERN clinical centre leads, hospital administrators, and national health authorities (JARDIN Joint Action, Work Package 9) to evaluate national support for ERN centres across six domains: staffing, education, formal recognition, funding, quality assurance, and strategic planning. Survey results revealed inconsistent national legal frameworks for recognizing ERN centres, major staffing deficits, and limited dedicated funding for ERN activities. Strategic planning for rare disease networks was often lacking, and institutional support for ERN-related quality assurance and continuing education remained low. Notably, ERN membership was associated with increased educational activities for health professionals, but these initiatives often lacked sustainability due to insufficient protected time and resources. Overall, the findings highlight that embedding ERNs into national health systems will require formal recognition of ERN centres in policy, consistent funding, stronger institutional backing, and structured support mechanisms to address workforce and quality gaps, ensuring long-term sustainability of this collaborative rare disease network.
AIM:To describe the demographic characteristics and outpatient and inpatient procedures experienced by pediatric patients with neurofibromatosis type 1 (NF1) in the Unified Health System (SUS). METHODS:This was an observational and retrospective study using administrative data from the Brazilian Outpatient Information System (SIA/SUS) and Inpatient Information System (SIH/SUS), covering the period from January 2008 to August 2024. Patients with a diagnosis code of ICD Q85.0 before the age of 18 were included. Demographic variables, comorbidities, and procedures were analyzed using a descriptive approach. RESULTS:A total of 3748 patients with outpatient records and 1262 inpatient admissions were identified. The mean age was 9.7 years, with a slight male predominance (53%). There was a significant increase in the number of visits over time, especially in the Southeast and South regions. The highest proportion of SUS-recorded pediatric NF1 cases per 10,000 pediatric inhabitants was recorded in the Federal District (4.22) and the lowest in Sergipe (0.10). The most common outpatient procedures were diagnostic, with emphasis on magnetic resonance imaging and cranial tomography. In a hospital setting, 9.5% of hospitalizations required intensive care. In the Intensive Care Unit (ICU), lethality rate varied from 0 to 4.4%. CONCLUSION:Although rare, NF1 represents a high-complexity condition within SUS, with a substantial demand for specialized resources, particularly among pediatric patients. The high frequency of comorbidities and frequent need for ICU admissions highlight the clinical and healthcare burden of the disease. These findings underscore the need for public health strategies to promote early diagnosis, improve health information systems, and expand access to specialized care centers in order to reduce regional disparities and enhance comprehensive care for patients with NF1.
OBJECTIVE:To characterize the clinical phenotypes and identify the genetic etiology in four unrelated families affected by Turner-type X-linked intellectual disability (XLID). METHODS:Peripheral blood samples were collected from four probands and their parents. Genomic DNA was extracted, and a comprehensive genetic analysis was performed using trio-based Whole Exome Sequencing (WES) combined with low-pass Copy Number Variation sequencing (CNV-seq). Candidate variants were subsequently validated via Sanger sequencing. RESULTS:Genetic analysis identified distinct variants in the HUWE1 across the four families. Specifically, four distinct HUWE1 variants were identified across the families: a hemizygous c.10034 > T (p.Lys3345Met) in Family 1; a heterozygous c.9209G > A (p.Arg3070His) in Family 2; a heterozygous c.12688T > C (p.Phe4230Leu) in Family 3; and a hemizygous c.9070G > A (p.Ala3024Thr) in Family 4. In accordance with ACMG guidelines, the novel variants in Families 1, 3, and 4 were classified as "Likely Pathogenic" (PS2 + PM2_Supporting + PP2 + PP3). In contrast, the previously reported variant in Family 2 was categorized as "Pathogenic" based on the criteria PS2 + PM2_Supporting + PM5 + PP2 + PP3_Moderate. All probands were clinically diagnosed with Turner-type XLID. CONCLUSIONS:This study expands the pathogenic variant spectrum of HUWE1 and provides novel molecular evidence for the clinical diagnosis of Turner-type XLID. These findings are of significant value for genetic counseling, carrier screening, and prenatal diagnosis for the affected families.
Shwachman-Diamond syndrome (SDS1) is an autosomal recessive disorder principally characterized by exocrine pancreatic insufficiency, a mild to severe bone marrow failure, peripheral blood cytopenias and an increased risk of developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Since 1995 several cytogenetic studies were performed mainly in relation to the myelodysplastic/myeloproliferative risk, and recurrent chromosome changes in bone marrow (BM) were discovered. In this paper we extensively reviewed the cytogenetic studies in SDS patients, and the related significance highlighted over the years. The conclusions were drawn from analyses of our large Italian cohort by long-term monitoring (up to 27 years), together with a comprehensive review of the literature.
Fragile X syndrome (FXS) is classically caused by CGG repeat expansion in the FMR1 gene leading to gene silencing. We describe two unrelated patients with clinical features consistent with FXS but harbouring distinct molecular mechanisms. The first patient had a pathogenic intronic variant in FMR1, predicted to impair protein function, and no repeat expansion. The second patient carried a complete deletion of the FMR1 gene, resulting in loss of gene expression. Both individuals presented with developmental delay, intellectual disability, and behavioural manifestations typical of FXS. These cases expand the causal heterogeneity underlying a clinically recognizable phenotype. They reinforce the concept that comprehensive molecular testing beyond repeat expansion analysis is mandatory in individuals with a strong clinical suspicion of FXS, in absence of a typical CGG triplet expansion.
Age-related hearing loss (ARHL), or presbycusis, is a very common sensory disorder resulting from cumulative exposure to environmental factors, biological aging and a significant genetic component. Although most cases of ARHL result from the combined influence of numerous low-effect variants, the increasing number of monogenic forms has shown the importance of rare, highly penetrant mutations in ARHL. Advances in whole-exome and whole-genome sequencing have strengthened the evidence for monogenic contributions, identifying deleterious variants consistent with dominant, recessive, or mitochondrial inheritance patterns. These monogenic cases provide valuable insights into the molecular mechanisms underlying cochlear aging and the vulnerability of sensory cells. To date, several genes have been clearly identified as responsible for familial or sporadic late-onset hearing loss, including KCNQ4, GRHL2, ILDR1, EYA4, MYO6, MYO7A, TECTA, WFS1, CDH23, and TMC1. Mutations in these genes affect diverse biological pathways such as potassium recycling, epithelial integrity, transcriptional regulation, mechanotransduction, extracellular matrix stability, and hair cell maintenance-functions that are fundamental to the long-term preservation of hearing. It is important to note that there is a growing overlap between the genes involved in Mendelian deafness and the susceptibility loci identified in ARHL, suggesting the existence of common molecular mechanisms between early-onset hereditary deafness and some forms of progressive ARHL. Furthermore, new data highlight the role of epigenetic regulation, mitochondrial dysfunction, cochlear synaptopathy, and non-coding RNAs in hearing loss. Despite major advances, several challenges remain, including phenotypic heterogeneity, limited representation of non-European populations, and a lack of consistency in the reproducibility of results across studies. Distinguishing between subtypes of ARHL characterized by audiometry-including sensory, neural and synaptopathic, metabolic forms, will likely be essential for improving genetic analyses and precision medicine approaches. Moreover, although polygenic risk scores (PRS) represent a promising strategy for risk prediction, their clinical applicability remains limited. Overall, the integration of monogenic, polygenic, environmental, and epigenetic data will be essential for understanding the complex genetic architecture of ARHL and for developing future personalized therapeutic interventions.
BACKGROUND:Trichorhinophalangeal syndrome type I/III (TRPS I/III) is a rare autosomal dominant skeletal dysplasia caused by pathogenic variants of TRPS1. Although several European cohorts have been reported, data from East Asian populations remain limited and longitudinal growth patterns and treatment responses have not been systematically evaluated. METHODS:We conducted a retrospective single-center study of 20 unrelated children of Korean origin with molecularly confirmed TRPS I/III, between 2012 and 2024. The clinical, radiological, and genetic data were reviewed. Growth parameters were analyzed using Korean reference standards and genotype-phenotype correlations were explored. Treatment responses to recombinant human growth hormone (rhGH) and minoxidil were assessed descriptively. RESULTS:All the patients exhibited characteristic craniofacial features and cone-shaped epiphyses with variable skeletal involvement. Short stature (standard deviation score [SDS] of height < -2) was observed in 21% of patients. Bone age was delayed before 12 years of age but showed rapid advancement thereafter, accompanied by a decline in height SDS during adolescence (p = 0.017). Truncating variants were identified in 65% of patients, missense variants in exon 6 in 15%, and exonic deletions in 20%. Missense variants in exon 6 were consistently associated with severe brachydactyly, whereas the overall stature showed no clear correlation with genotype. Responses to rhGH and minoxidil treatments were variable. CONCLUSIONS:TRPS I/III demonstrated substantial phenotypic heterogeneity and age-dependent growth dynamics in this Korean cohort. Severe distal limb involvement was associated with exon 6 missense variants, whereas growth impairment remained variable. Long-term follow-up and multidisciplinary management are essential to optimize clinical outcomes.
The gold standard recommendation for congenital sensorineural hearing loss (SNHL) care is cochlear implantation (CI). Adjusting for confounding factors such as developmental comorbidities is crucial when assessing expected outcomes of the procedure for the patients, their families, and their medical teams. We describe two clinical cases of the deafness and onychodystrophy (DOD) spectrum and the benefit of molecular diagnosis to underline the importance of genetic testing when evaluating potential CI outcomes in syndromic congenital SNHL.
CACNA1G encodes the Cav3.1 T-type calcium channel, a key regulator of neuronal excitability and thalamocortical rhythmicity. Pathogenic variants have been associated with neurodevelopmental disorders, frequently accompanied by epilepsy and cerebellar abnormalities. We report a patient with global developmental delay and autism spectrum disorder who developed progressive gait instability and was found to harbor a novel de-novo CACNA1G variant, c.4658G > A p.(Arg1553Gln). Notably, the patient had no history of seizures and normal electroencephalographic findings. Brain magnetic resonance imaging revealed cerebellar and vermian hypoplasia, consistent with previously described cases, as well as an incidental intracranial lipoma. Distinctive clinical features included macrocephaly and appendicular hypertonia, findings not previously reported in association with CACNA1G-related disorders and potentially expanding the phenotypic spectrum. The identified variant is located in the intracellular III-IV linker region of Cav3.1, outside the canonical pore-forming domains where most epilepsy-associated variants cluster. Its absence from the literature and public variant databases supports its novelty. This case broadens the clinical and molecular spectrum of CACNA1G-related disease and highlights phenotypic variability, particularly in patients without epilepsy.
Genetic testing plays a pivotal role in the management of Inherited Retinal Diseases (IRDs), yet a significant proportion of patients remain without a molecular diagnosis. This study aimed to develop a predictive matrix to estimate the likelihood of diagnostic success in order to manage patient expectations prior to genetic testing. Conducted as a retrospective, single-center cohort study, it analyzed data from 1001 IRD patients across 804 unrelated families enrolled in the IRD-PT registry. Key clinical variables-including age at symptom onset, family history, consanguinity, and referral timing-were evaluated for their association with genetic diagnostic yield. Results showed that 68.03% of families received a solved diagnosis, while 11.19% were likely solved. The presence of consanguinity, a positive family history, or childhood symptom onset significantly increased the probability of a solved diagnosis (up to 81.7%), whereas their absence reduced it to 31.2%. The study culminated in the creation of a conditional probability model that stratifies patients by their likelihood of molecular confirmation. This tool offers clinicians a practical, evidence-based approach to pre-test genetic counselling, enhancing transparency and expectation management for patients undergoing IRD genetic testing.
For decades, the diagnosis of rare genetic disorders has relied on a phenotype-driven approach, often resulting in a prolonged "diagnostic odyssey." The widespread use of whole-exome and whole-genome sequencing has transformed this paradigm, increasingly enabling genotype-first diagnoses before a clear clinical phenotype is recognized. This shift may contribute to a reversal of the diagnostic odyssey, in which genetic findings guide subsequent clinical evaluation through reverse phenotyping. Large-scale biobank studies and newborn genomic screening programs are further accelerating this paradigm shift. Although this approach has improved diagnostic yield, it also introduces interpretative challenges, including the risk of phenotype reinterpretation bias and the persistent burden of variants of uncertain significance (VUS), particularly when genetic variants only partially explain the clinical presentation. This article discusses the emergence of genotype-driven diagnosis and emphasizes the need for balanced integration of genomic and clinical data in modern precision medicine.
Pathogenic variants in BAF complex genes are linked to neurodevelopmental disorders, termed BAFopathies. Coffin-Siris syndrome (CSS) is the most well-defined BAFopathy caused by variants in several BAF subunit genes. ARID1A variants are responsible for 6-8% of CSS cases. We report a female individual with clinical and phenotypic manifestations suggestive of CSS. Trio exome sequencing failed to identify a causative variant. Short-read genome sequencing revealed a de novo 24 kb intronic deletion in ARID1A. Methylation analysis showed a BAFopathy-like profile supporting pathogenicity. Transcriptome analysis and RT-PCR detected a rare aberrant splicing event in a subset of ARID1A transcripts: the activation of a pseudoexon, resulting in a premature termination codon as the underlying pathomechanism. This is the first non-coding pathogenic alteration reported in ARID1A and the second in a CSS gene. This case highlights how the combination of genomic, transcriptomic and epigenomic data is crucial to improve diagnostic accuracy in unsolved cases.
Medical understanding of rare diseases is hindered by incomplete initial descriptions. A related but often overlooked question is how many patients are required to define a phenotype. We evaluated the phenome coverage of 10 recently published gene-disease associations using the Human Phenotype Ontology (HPO) system as a template and calculated the sample sizes required to significantly associate the prevalence of a given trait with particular phenotype. The phenome coverage of the studied descriptions was below 50% in all cases (range 4 to 43%, median, 26%) and the number of patients described (median, 3; range 1 to 17 patients) was insufficient to establish all but very strong associations (relative risks >5). These results highlight the importance of thorough phenotyping on the one hand, and of continued publication of case reports on the other, even after a disease is thought to be well known.
INTRODUCTION:Ritscher-Schinzel syndrome (RTSC; 3C syndrome) is a rare syndromic neurodevelopmental disorder resulting from defects in endosomal recycling. Biallelic variants in VPS35L, encoding a core component of the Retriever complex, have only recently been implicated in RTSC. METHODS:Trio-based-whole exome sequencing was performed in a male infant with classical RTSC features. Variant pathogenicity was assessed using population databases, multiple in-silico predictors, structural modeling, and splicing analyses. Segregation analysis was performed in the parents. RESULTS:A novel homozygous VPS35L variant (NM_020314.7: c.881T > C; p.(Phe294Ser)) affecting a highly conserved residue was identified. The variant is absent from population databases and is predicted to be deleterious. Structural modeling and stability calculations indicate a marked destabilizing effect, whereas splicing predictions do not support a major effect of nucleotide change on canonical splice site usage. Clinically, the patient exhibited cerebellar, craniofacial, skeletal, and cardiac anomalies with severe postnatal growth retardation. CONCLUSIONS:This patient provides additional evidence supporting the pathogenic role of VPS35L in RTSC and expands the emerging molecular and clinical spectrum of VPS35L-related disorder, highlighting the value of detailed genotype-phenotype correlation in ultra-rare syndromes.
Bannayan-Riley-Ruvalcaba syndrome is a rare PTEN-related disorder characterized by macrocephaly, intellectual disability, autism, hamartomatous intestinal polyps, and pigmentation of the glans penis. We describe a novel pathogenic variant of PTEN, c.48del (p.Gln17LysfsTer7), along with the first description of hepatic glycogenosis and steatosis in a child with BRRS. We proposed that the mutation likely led to a release of the inhibition of the insulin signaling pathway in the liver, leading to increased glycogen production and de novo synthesis of fatty acids, as previously shown in mice. Our data further extend possible metabolic complications of PTEN-related disorder.
Background Metaphyseal anadysplasia 1, which includes Spondyloepimetaphyseal dysplasia Missouri type, is a rare autosomal dominant skeletal dysplasia characterized by short stature, mild limb deformities, and transient metaphyseal irregularities that typically resolve with age. The condition is caused by heterozygous missense variants in the MMP13 gene, encoding matrix metalloproteinase 13, a key enzyme in endochondral ossification and extracellular matrix remodeling. Pathogenic variants in MMP13 are exceedingly rare, with only a few families reported. Case Presentation We report two siblings, aged 3 and 1 years, in Sweden, presenting with clinical and radiological features consistent with Metaphyseal anadysplasia 1. Their father, of Syrian origin, exhibited short stature and mild femoral bowing. Genetic analysis revealed a novel heterozygous missense variant c.217T>C, p.(Ser73Pro) in MMP13, inherited from the affected father, and located within the same MMP13 domain as previously reported patients. The family pedigree demonstrates multiple affected individuals with short stature and bowed femurs, consistent with autosomal dominant inheritance. Radiographic imaging of father confirmed persistent but mild skeletal abnormalities. Conclusion This report expands the genotypic spectrum of Metaphyseal anadysplasia 1 and suggests a putative mutational hotspot in exon 2. It further emphasizes the importance of thorough clinical, radiological, and genetic evaluation in families with short stature and metaphyseal irregularities and a clinical long-term follow-up is proposed with regular radiographic monitoring.
Monoallelic pathogenic variants consistent with Mendelian inheritance patterns causing congenital heart disease (CHD) have been increasingly identified as genetic testing, including genome sequencing (GS), has become more widely available within the clinical space. Here, we focus on a newly described pathogenic variant in CDH2 resulting in Agenesis of Corpus Callosum (ACC), Cardiac, Ocular, and Genital Syndrome (ACOGS). While previous studies document variable expressivity of the CDH2 variants in unrelated individuals, no cases have described such variable expressivity in twins with the same CDH2 variant. We present a novel case of likely monozygotic twins who both carried the same pathogenic CDH2 variant yet exhibited a spectrum of CHD with one presenting with hypoplastic left heart syndrome and the other with ventricular septal defect and pulmonary hypertension.
