Orphanet Journal of Rare Diseases

Background: Hereditary transthyretin amyloidosis (hATTR) manifests as cardiomyopathy and/or polyneuropathy. The V142I variant predominantly causes cardiac disease in African Americans, though neurological involvement may be underrecognized. We characterized neuropathy documentation and treatment patterns in a predominantly V142I cohort. Methods: Retrospective review of 54 hATTR patients at a major academic medical center. Neuropathy was classified as: objective (abnormal EMG), possible polyneuropathy (documented symptoms suggestive of polyneuropathy), symptoms only (neuropathic symptoms without specialist evaluation), or unclear. Treatment with stabilizers (tafamidis, acoramidis, diflunisal) and gene silencers (patisiran, vutrisiran, eplontersen) was assessed. Results: Of 54 patients (88.9% African American, 85.2% V142I), 51 (94.4%) had confirmed cardiac involvement. Among cardiac patients, 40/42 eligible (95.2%) received stabilizers. Overall, 16 patients (29.6%) received gene silencers, with 13 (24.1%) receiving both a stabilizer and gene silencer concurrently. Possible neuropathy (objective, possible polyneuropathy, or symptoms) was documented in 30 patients (55.6%). Gene silencer use was highest among those with objective neuropathy (8/17, 47.1%) versus symptoms only (1/10, 10.0%). All three patients without confirmed cardiac disease received gene silencers. Conclusions: In this V142I-predominant cohort with 94.4% cardiac involvement, stabilizer use was high (95.2%) among eligible patients. Over half had possible neuropathy based on clinical documentation, though EMG completion was limited (57.4%). Gene silencer use was associated with objective neuropathy documentation and non-cardiac phenotype. These findings support systematic neurological assessment in hATTR, even when cardiac disease predominates.

Background: Diagnosing the over 700 known rare bone diseases (RBDs) is inherently challenging and often requires extensive time and multiple clinical visits. Effective treatment, particularly for RBDs with approved therapies, depends on early and precise identification of the specific RBD type. Image recognition artificial intelligence (AI) has the potential to significantly enhance diagnostic processes and improve patient outcomes. Many of these disorders cause characteristic skeletal changes, especially in the hands, and are associated with growth abnormalities. Consequently, affected children routinely undergo hand radiographs for bone age assessment, making these images a widely available yet underutilized diagnostic resource. Materials and Methods: We retrospectively compiled 5,623 multi-institutional hand radiographs from 2,471 patients with 45 different RBDs and 1,382 unaffected controls. We trained two deep learning models: a binary classifier to differentiate between RBD and non-RBD hand radiographs, and a multi-class classifier covering ten RBDs (or RBD groups), using 5-fold cross-validation. Preprocessing included masking, normalization, and data augmentation. Additionally, we applied occlusion sensitivity mapping to visualize class-specific features and evaluated the learned representations through cosine-based retrieval and UMAP projections of the feature space. Results: The affected versus unaffected classifier achieved a balanced accuracy of 85.5% on the test dataset. The ten-class classifier reached a balanced (top-1) accuracy of 76.6%, with top-3 accuracy exceeding 90%. Disorders with highly distinctive phenotypes, such as achondroplasia, achieved accuracies above 95%, whereas phenotypically overlapping disorders, such as ACAN- and SHOX-related short stature, were more frequently confused. Feature space analysis showed that validation samples clustered closely with their respective training distributions, supporting the consistency and generalizability of the learned embeddings. Conclusion: This manuscript presents a proof of principle for the development of Bone2Gene, a next-generation phenotyping (NGP) tool for the detection and differential diagnosis of RBDs, currently based on hand radiographs. Ongoing efforts focus on expanding the dataset to include additional RBDs or RBD groups in the current multi-class classifier for differential diagnosis and to further evaluate its generalizability. The Bone2Gene study is open to collaboration.

Background: Facioscapulohumeral muscular dystrophy (FSHD) is a common hereditary neuromuscular disorder. The Russian FSHD Patient Registry was established in 2019 following the development of a PCR-based method for genetic confirmation of the diagnosis. Results: The registry included 470 participants (51% male). Genetic confirmation was obtained for 76% (n=356), the remainder were included based on clinical and anamnestic data. Clinical assessment forms and patient-reported questionnaires were analyzed for 310 and 142 patients, respectively. D4Z4 repeat unit (RU) distribution showed patterns consistent with European cohorts, with a predominance of patients with 3 RUs. A moderate inverse correlation was found between RUs number and clinical severity scales. Periscapular weakness was the most common onset manifestation (46.8%), followed by facial weakness (31.6%) which was often unnoticed by patients. The mean age in the Russian cohort was 37.8 years (range 0-97), indicating a younger cohort compared to international data. A delta-adjusted cluster analysis (n=215) identified three distinct trajectories: a classic phenotype with onset before age 14 and early involvement of various muscle groups (n=177), and two clusters characterized by either facial or periscapular onset with slow progression. Conclusion: The Russian FSHD registry provides a comprehensive characterization of a large national cohort, revealing a predominance of patients with 3 D4Z4 repeats and a younger demographic profile compared to international data. Cluster analysis identified three heterogeneous disease trajectories, offering a framework for improved patient stratification.

Importance: NGLY1 (N-Glycanase 1) Deficiency is an ultra-rare autosomal recessive disorder affecting ~165 patients worldwide, characterized by developmental delay, hyperkinetic movement disorders, and shortened life expectancy. Despite its severe neurological manifestations, comprehensive neuroimaging characterization has been limited to case reports and small descriptive studies. Objective: To investigate alterations in brain morphology in patients with NGLY1 Deficiency and determine whether these metrics associate with clinical phenotypes. Design, Setting, and Participants: This case series analyzed real-world MRI scans performed on 11 patients with NGLY1 Deficiency between 1999-2023 at sites across the globe. Ages ranged from 2 to 19 years at scan time (5 female, 6 male). Exposure: Molecular diagnosis of NGLY1 Deficiency. Main Outcomes and Measures: Cortical and subcortical morphology, including subcortical volume, and cortical thickness, surface area, volume, and curvature, were measured with 3-dimensional T1-weighted magnetic resonance imaging (MRI) scans. Z-scores were calculated using normative models from CentileBrain for patients >3 years old or custom models for patients <3 years old. Clinical phenotypes were matched to Human Phenotype Ontology codes. Results: 16 scans from 11 patients met quality criteria for analysis. Both age groups (under and over 3 years old) showed significantly reduced subcortical volumes, particularly in bilateral thalamus and putamen. Younger patients demonstrated widespread reductions in cortical surface area, volume, and curvature, indicating altered gyrification patterns. Older patients showed thinner dorsal and thicker ventral cortical regions with limited surface area reductions. Thalamic volume reduction in older patients correlated with gait disturbance, dysphagia, and EEG abnormalities, with additional cortical associations with sleep and hearing abnormalities. Seizure presence in younger patients correlated with altered cortical thickness, surface area, and curvature patterns. Conclusions and Relevance: NGLY1 Deficiency is associated with pervasive alterations in brain development affecting both subcortical and cortical morphology. Age-dependent patterns of cortical alterations indicate disrupted neurodevelopmental trajectories that may reflect impaired neuronal migration and/or altered synaptic pruning. Correlations with clinical variables suggest that these measures may serve as useful biomarkers for tracking disease progression and/or treatment efficacy. These findings provide a comprehensive neuroimaging characterization of NGLY1 Deficiency and establish a foundation for understanding brain structure-function relationships in this ultra-rare disorder.

Background: Rett Syndrome (RTT) is a severe neurodevelopmental disorder affecting approximately 1 in 10,000 live female births worldwide. The Rett Syndrome Behaviour Questionnaire (RSBQ), remains one of the most widely used standardized behavioral assessment tools for RTT. However, the RSBQ was originally validated only in British English, limiting its applicability for Spanish-speaking caregivers and clinical centers across Latin America and Spain. Objective: The primary aim of this study was to develop and validate the comprehension of the Spanish translation of the RSBQ to ensure cultural and linguistic equivalence, enhance data reliability, and facilitate earlier, more accurate clinical assessments among Spanish-speaking RTT populations. Methods: Surveys were administered in two phases to Spanish-speaking caregivers between November 2023 and September 2025. Phase I consisted of 12 guided survey administrations with participants being able to ask clarifying questions and offer linguistic modifications of RSBQ questions. Phase II consisted of independent online administration of the refined Spanish RSBQ and a retest at least 7 days later. Participants were recruited through direct outreach and supported virtually during questionnaire completion. Results: Following data cleaning and quality control, a total of 51 caregivers successfully completed both surveys. The Spanish RSBQ demonstrated high caregiver comprehension and strong engagement across multiple Latin American countries, including Argentina, Mexico, and Peru. Responses were highly correlated between test and retest timepoints, and no question showed biased response distributions. A slight effect of response interval on test-retest correlation was observed, potentially indicating the impact of natural disease progression confounding retest evaluation for long (>80 day) intervals; however this effect did not impact the overall linguistic validation results as analysis of only <21 day test-retest responders confirmed the findings. Conclusions: This linguistic validation study represents the first formal step toward the clinical validation of the Spanish RSBQ, enabling broader inclusion of Spanish-speaking populations in RTT research. The collaborative, bilingual data collection strategy proved both feasible and effective, paving the way for multinational trials and expanding therapeutic accessibility through localized, patient-centered innovation.

Background Cardiac MRI (CMR) is often utilized for patients with suspected cardiac amyloidosis (CA). However, data are lacking for use in patients with advanced renal dysfunction (ARD) (GFR<30 mL/min/1.73 m2, dialysis dependent, or renal transplant). This study evaluates the utility of CMR for diagnosis of CA in this population. Methods Patients with ARD who underwent CMR in a 3T field for suspicion of CA between 2010 and 2024 at our institution were included. A diagnosis of CA was made if any of the following were present a)?PYP scintigraphy grade ? 2, b) positive endomyocardial biopsy, or c) positive extracardiac biopsy with clinical features of CA. Two CMR-trained physicians independently assessed T1 relaxation time, ECV, Ti scout, LGE, and overall likelihood of CA. Results Out of the 65 patients included 14 (22%) had a diagnosis of CA. Although T1 time [1352 (1276-1428) ms] and ECV (40.3% +/- 9.1%) were elevated across the cohort, they were significantly higher in patients with CA (p<0.001 for both). Both ECV and T1 time reliably predicted CA (AUC of 0.87 and 0.88 respectively). ECV of ?45% had 75% sensitivity and 80% specificity for CA. A T1 time ? 1390 ms had 75% sensitivity and 85% specificity for CA. LGE was prevalent and was seen in 86% and 84% patients with and without CA respectively. Of the 31 patients deemed to be unlikely CA by a CMR reader, 6% had CA. However, of the 34 patients read as possible/likely CA, only 35% had confirmed CA. Conclusions In this understudied population of ARD, CMR parametric mapping exhibits high negative predictive value (NPV) for CA and improved positive predictive value (PPV) when higher cutoffs are used for T1 time and ECV. CMR reader overall impression exhibits high NPV but low PPV for CA.

OBJECTIVE: Anthropometric data are critical in paediatric care, routinely assessed during clinical visits, and available in electronic health records (EHRs). We describe the feasibility of extracting anthropometric data from heterogeneous EHR systems of Swiss childrens hospitals, evaluate their availability and quality, and assess the cohorts representativeness of the general population. METHODS: In this multicentre study (SwissPedGrowth), we retrospectively collected EHRs from patients <20 years who visited hospitals in Basel, Bern, Geneva, Lausanne, Luzern, St. Gallen, or Zurich between 2017-2023. Sociodemographic, administrative, and clinical information from EHRs were provided in a standardized way by a paediatric national data stream (SwissPedHealth), including the Swiss Neighbourhood Index of Socioeconomic Position (Swiss-SEP). We counted anthropometric recordings per visit to describe availability and used a self-developed and an existing (growthcleanr) algorithm to investigate data quality. To assess representativeness, we compared sociodemographic characteristics between SwissPedGrowth and the general paediatric population in Switzerland, computed standardized differences (effect size: 0.2 small, 0.5 medium, 0.8 large), and weighted the study population to reduce differences. RESULTS: We included 477,531 patients and 2,171,633 hospital visits; 54% boys, 71% Swiss, mean Swiss-SEP 65 (SD: 11), and median age at visit 6.3 [IQR: 2.3, 11.8] years. Height recordings were available for 20% of the visits, weights for 43%, and head circumferences for 5%, with better availability for inpatient stays than outpatient or emergency visits. Combining the self-developed and existing algorithm, 4% of heights and 3% of weights were flagged as outliers and 29% of heights and 31% of weights as carried forward from previous visits or same day duplicates. Sociodemographic differences between SwissPedGrowth and the general population were small or small-to-medium and disappeared after weighting. CONCLUSION: SwissPedGrowth demonstrates feasibility of extracting high-quality anthropometric data for paediatric growth research, but challenges regarding completeness and harmonization of EHR data across Swiss hospitals remain.

Dystonia treatment evaluation in cerebral palsy (CP) is limited by the lack of clinician-assessed scales linking dystonia severity to functional impact. We asked 7 pediatric movement disorder specialists to review videos of 27 children with CP while performing an upper extremity task and while walking. Experts rated arm and leg dystonia severity using the Global Dystonia Severity Rating Scale (GDRS) and task-specific functional impact on a five-point scale adapted from the Dyskinetic Cerebral Palsy Functional Impact Scale. Arm GDRS scores correlated with functional impact on the upper extremity task (linear regression R^2=0.48, p=0.0005). Leg GDRS scores correlated with gait impact (R^2=0.43, p=0.001). A four-point increase in total GDRS corresponded to a one-point worsening in combined functional impact. By demonstrating how expert-rated limb dystonia severity correlates with task-specific functional impact in children with CP, these results could help clinically identify functionally-meaningful differences in dystonia severity.

As therapeutic options emerge for hereditary spastic paraplegias (HSP), clinical trials require outcome measures that reflect disease aspects most important to patients. Patient priorities in HSP remain poorly defined. This study aimed to develop a regulatory-compliant framework of patient-prioritised health domains to evaluate treatment response in clinical trials. Patient-reported data on health impacts were collected via two multinational, multilingual online surveys conducted sequentially, including 616 and 504 patients across the clinical and genetic spectrum of HSP. Using a staged approach, we examined prevalence, relevance, and severity, focusing on health impacts that were (i) common (ii) sensitive to disease progression, (iii) highly relevant to patients, and (iv) showed strong severity-relevance correlation. Patient representatives contributed centrally to study design and prioritisation. Our patient-focused analysis yielded five highly prevalent and relevant core health domains: mobility, lower body function, autonomic dysregulation, pain, and psychosocial aspects. Ambulation and lower body function ranked highest across all disease stages. Among non-motor impacts, reduced ability to work, bladder incontinence, and fatigue were most relevant. In mild disease stages, reduced walking distance, reduced walking speed, and the urgency to empty the bladder were the most frequent and most relevant health impact. This work provides the most comprehensive patient-reported and disease stage specific profiling of HSP health impacts to date. It lays the necessary groundwork for developing patient-focused outcome tools capable of capturing treatment effects in future trials.

Background: Saudi Arabia bears a disproportionate burden of autosomal recessive genetic disorders, driven by consanguineous marriage rates of 50 to 58% and elevated carrier frequencies for conditions such as sickle cell disease (carrier rate up to 25%), betathalassemia (12%), and spinal muscular atrophy (6%). The existing premarital screening program screens for only two conditions. We developed SafeGene, a computational platform that expands predictive genetic screening to 50+ conditions using region specific population genetics. Methods: SafeGene integrates five risk calculation engines: (1) Mendelian inheritance models for AR, AD, XR, and XD conditions; (2) Hardy Weinberg equilibrium based carrier probability estimation using Saudi, Gulf, and global databases; (3) a six level consanguinity coefficient calculator (F = 0 to 1/8) with risk amplification multipliers; (4) multifactorial polygenic risk models for 12 complex diseases; and (5) maternal age dependent trisomy risk curves. Built using React.js, Node.js/Express, and MongoDB with bilingual Arabic/English support. Results: The platform encompasses 50 genetic conditions across 12 categories. Validation against published Saudi data demonstrated concordance with observed disease frequencies. Economic modeling projects that expanding screening could prevent 2,800 to 4,200 affected births annually, yielding savings of SAR 1.2 to 2.8 billion ($320 to 746 million USD) per year. Conclusions: SafeGene represents a scalable, evidence-based digital health solution for comprehensive genetic screening addressing the unique population genetics of consanguineous Gulf societies. The platform is protected under pending patent applications in South Africa (CIPC) and Saudi Arabia (SAIP).

Objective The decline of the perinatal demise rate is slowing and demises are often unexplained. Significant research has been done regarding diagnostic yield and genetic causes of demise, but little is known about how Geneticist involvement impacts outcomes. The goal of the study was to evaluate post-mortem genetic testing practices and effects of the geneticists involvement. Methods Retrospective data from 111 perinatal demise cases was examined, including rates of prenatal genetic counseling, post-delivery genetics consult, genetic testing, and autopsy investigation. Results In this cohort 54% received genetic testing and 25% received a genetics consult. When compared to those without, cases with genetic specialist involvement were associated with significant increases in testing uptake (p=0.007), diagnostic yield (p<0.001), and patient education (p<0.001). Second trimester stillbirths and those with fewer ultrasound (US) abnormalities were less likely to receive genetic testing (both p values <0.001) and consults (p<0.001, p=0.020). Conclusion Though it was not possible to avoid ascertainment bias, this data demonstrates that geneticist involvement correlates with a higher rate of testing, greater diagnostic yield, and more thorough counseling. These findings underscore the importance of integrating genetics providers into perinatal postmortem healthcare teams.

Objective Cerebral palsy (CP) affects approximately 1 million Americans and 18 million individuals worldwide, yet contemporary US epidemiologic data remains limited. We aimed to use Cerebral Palsy Research Network (CPRN) clinical registry to describe demographics and clinical characteristics of individuals with CP across the US and determine associations with gross motor function and genetic etiology. Methods Registry subjects were included if they had clinician-confirmed CP and prospectively entered data for Gross Motor Function Classification System (GMFCS) Level, gestational age, genetic etiology, CP distribution, and tone/movement types. Logistic regression was used to determine which of these variables plus race, sex, ethnicity, and age were associated with GMFCS level and genetic etiology. Results A total of 9,756 children and adults with CP from 22 CPRN sites met inclusion criteria. Participants were predominantly White (73.0%), male (57.3%), non-Hispanic (87.8%), and younger than 18 years (73.7%). Most were classified as GMFCS levels I-III (55.6%), born preterm (52.8%), had spasticity (83.8%), and had quadriplegia (41.9%); 12.2% were identified as having a genetic etiology. Tone/movement types, CP distribution, and gestational age were significantly associated with both GMFCS level and genetic etiology (p<0.001). Compared to White individuals, Black individuals were more likely to have greater gross motor impairment (p<0.001). Conclusion In this large US cohort, clinical and demographic factors, including race, were associated with gross motor function and genetic etiology in CP. These findings highlight persistent disparities and demonstrate the value of a national clinical registry for informing prognostication, quality improvement efforts, and targeted genetic testing strategies.

BackgroundAlthough neurogenic orthostatic hypotension (nOH) is a common and debilitating feature of multiple system atrophy (MSA), little is known about the burden of symptoms in the real world. ObjectivesTo design and conduct a cross-sectional community-based research survey targeting patients with MSA, with and without nOH. MethodsWe recruited patients with MSA to complete an anonymous online survey covering three core themes: 1) timely diagnosis, 2) nOH pharmacotherapy and refractory symptoms, and 3) confidence in physician knowledge. Responses were grouped by pre-specified diagnostic certainty levels. Relationships between symptoms, function, and pharmacotherapy were assessed using univariate and multivariate methods. ResultsWe analyzed 259 respondents with a self-reported diagnosis of MSA (age: M=64.38, SD=8.09 years; 44% female). In total, 42% also had a diagnosis nOH; 40% had symptoms highly suspicious of nOH, but no diagnosis; and 21% reported having never had their blood pressure measured in the standing position at a clinical visit. Treatment with a pressor agent was independently associated with the presence of other symptoms of autonomic failure. Each additional nOH symptom reported increased the odds of requiring pharmacotherapy by 18%. Yet, despite anti-hypotensive medication use, 97% of patients reported limitations in their ability to bathe, cook, or arise from a chair/bed with 76% needing caregiver support for refractory nOH symptoms. ConclusionsThis cross-sectional representative sample shows nOH is underrecognized and undertreated in MSA patients, leading to substantial functional limitations. It is our hope that these findings are leveraged for planning future trials and advocating for better treatments.

Background Education outcomes predict life chances. However, poverty, ill-health and disability are barriers to achievement. We examined determinants of academic attainment of children with and without major congenital anomalies in state-funded mainstream schools at ages 11 and 16 (key stages [KS] 2 and 4). Methods and Findings Routinely collected electronic records for children born in Wales 01/01/1998-31/12/2007 until 31/12/2019 were linked in the Secure Anonymised Information Linkage (SAIL) Databank. Education outcomes were explored using logistic regression, adjusting for: anomalies, maternal and child deprivation, prescribing, hospitalisation, gestation length, childs sex, and special education needs (SEN) provision. Children with anomalies were less likely to achieve academic standards: however, attainment was more closely associated with affluence. At age 11, 81.87% (7167/8754) with and 93.80% (232,450/247,814) without anomalies passed (odds ratio [OR] 0.30, 95% confidence intervals [CI] 0.28-0.32). At age 16, 46.76% (2070/4427) with and 56.10% (69,732/124,300) without anomalies achieved 5 General Certificates of Secondary Education (GCSEs) at grades C-A* including English/Welsh, Maths and Science (EWMS) (OR 0.69, 0.65-0.73). Discrepancies narrowed in adjusted analyses, particularly when SEN provision was accounted: aOR 0.72 (0.66-0.78) at KS2, and aOR 0.93, (0.87-1.00) for 5 GCSEs C-A* with EWMS. These GCSEs were achieved by 29.65% (307/1034) children with anomalies and 38.42% (10,875/28,305) of unaffected children in the most deprived quintile{dagger}: in the most affluent quintile, figures were 67.57% (547/810) and 74.98% (16,978/22,644). Children with anomalies, receiving maximum SEN support, eligible for Free School Meals (FSM) were the least successful: 5/192 (2.6%) passed 5 GCSEs C-A* with EWMS, as did 37/354 (10.4%) ineligible for FSM. The strongest associations with these GCSEs were SEN statements (aOR 0.07, 0.06-0.07), FSM eligibility (aOR 0.39, 0.37-0.41), and epilepsy (aOR 0.60, 0.45-0.80). However, data were unavailable for 15-18% of children, mainly those educated outside mainstream schools, and some co-morbidities. Generalisation of findings to other countries rests with readers. Conclusions Many children with anomalies from affluent households succeeded. The children left behind lived with poverty and ill-health from congenital anomalies and/or epilepsy. SEN provision mitigated the impact of disadvantage, but poor children with anomalies were unlikely to succeed. {dagger}taking maternal Welsh Index of Multiple Deprivation (WIMD) 2014 at birth.

Hypospadias, a common congenital anomaly requiring surgical correction, has seen growing research in surgical techniques and outcomes. However, no comprehensive bibliometric or disruption-based analysis exists to map the fields evolution. This study uses bibliometrics and the Disruption Index (DI) to identify key transformational research in hypospadias. A systematic search of five databases (PubMed, Web of Science, ScienceDirect, Scopus, and Dimensions) from January 1990 to December 2023 was conducted, yielding 7,732 articles. After applying inclusion criteria, 200 studies were analyzed. Citation data and DI scores were calculated using OpenCitations. Spearmans rank test assessed correlations between DI and citation metrics. A subgroup analysis identified trends based on the latest hypospadias research priorities. The mean citation count was 72.3 (SD = 43.1) with a mean DI of 0.011 (SD = 0.17). Five studies, focusing on complications, analgesia, and surgical techniques, had the highest DI (1.0). A moderate positive correlation was found between DI and citation rate ({rho} = 0.405, p < 0.001). Subgroup analysis showed most research focused on surgical techniques (30.5%) and etiology (25.8%), while areas like surgical training (2.6%) and innovation (0%) were underrepresented. This study identifies critical gaps in hypospadias research. The DI reveals influential studies that redirect research trajectories. Future work should focus on innovation and translational research to accelerate advancements in hypospadias care.

BackgroundPleuroparenchymal fibroelastosis (PPFE) is a rare, fibrotic lung disease with poor prognosis, usually affecting adults which most commonly occurs idiopathically. Biallelic pathogenic variants in DGUOK cause mitochondrial DNA (mtDNA) depletion syndrome, predominantly affecting infants with severe hepatic and neurological symptoms. Detailed description of pulmonary manifestations with late-onset presentation have not been reported. MethodsWe describe nine patients with PPFE and DGUOK-associated mitochondriopathy. Clinical, radiological, histopathological, and genetic data were systematically collected from all patients. Functional studies, single nucleus RNA sequencing (snRNAseq), immunofluorescence staining, transmission electron microscopy and respiratory chain enzyme activity assays were conducted on patient-derived fibroblasts, muscle or lung tissues. mtDNA content quantification was performed on whole genome sequencing (WGS) data. ResultsAll patients (ages 5-36) presented with progressive dyspnea, weight loss and some with spontaneous pneumothoraces. Chest computed tomography and lung biopsies showed features of PPFE. Biallelic pathogenic DGUOK variants were identified in all patients, seven of them carry an unreported intronic variant leading to mtDNA depletion. snRNAseq of lung tissue from four pediatric patients identified Aberrant Basaloid cells and intermediate cells as their precursor localized at the fibrotic edge. Mitochondrial alterations were identified by electron microscopy. ConclusionPPFE in children and young adults is associated with DGUOK-related mitochondriopathy. For the first time, we demonstrate Aberrant Basaloid cells in pediatric fibrotic lung tissue. Since pulmonary involvement may be underrecognized or misinterpreted and the clinical presentation may not always be typical of a mitochondriopathy, we recommend genetic testing in all patients with PPFE of unknown origin.

Background: Clinical genetic evaluation for patients with dilated cardiomyopathy (DCM) is minimally implemented and models of care are not defined. To understand current genetics care for DCM, a systematic needs assessment was conducted. Methods: Principal Investigators (PIs) of the DCM Consortium convened at the Summer Scientific Symposium in July 2025. An electronic needs assessment was collected from the 24 PIs in advance to define current care models by evaluating which Heart Failure Society of America-recommended genetic evaluation components are conducted, by whom, and time required. Descriptive statistics were generated to characterize model features. Focus group discussions explored barriers and facilitators to implementing genetic services. Results: Four care models emerged from the PI responses: 1 -- Traditional-Synchronous (25%, n=6, requiring the most time per patient), 2 -- Traditional-Asynchronous (33%, n=8), 3 -- Externally Sourced (17%, n=4), and 4 -- Physician/Advanced Practice Provider Conducted (25%, n=6, requiring the least time per patient). All models used genetic testing, whereas other components were implemented variably or not at all. Models 1 (15.7{+/-}4.1) and 2 (15.4{+/-}3.0) were rated more acceptable than Model 4 (9.8{+/-}2.9, 1 vs 4: p=0.027; 2 vs 4, p=0.023). Notably, 88% of PIs used genetic information for treatment decisions, including ICD placement (83%; n=20) or cardiac transplant (63%; n=15). Major facilitator themes from focus group discussions included having a genetic counselor on the HF team and developing authoritative standards directing provision of DCM genetic services. Barrier themes included operational challenges, limited personnel, clinician under-recognition, need for new service delivery models, and billing/reimbursement. Conclusions: DCM genetic care models and components were highly variable across the 24 sites of the DCM Consortium, even though all sites discussed similar factors that enable or hinder implementing genetic services for DCM. Understanding the basis of practice model variability may provide insight to yield more scalable care approaches.

Abstract Background Understanding the phenotypic spectrum of disease-associated genes is essential for accurate diagnosis and targeted therapy. FRMPD4 (FERM and PDZ Domain Containing 4) has previously been associated with intellectual disability and epilepsy. However, its potential role in non-syndromic hearing loss has not been explored. Methods We performed genetic analysis in two unrelated families presenting with non-syndromic sensorineural hearing loss, identifying maternally inherited missense variants in FRMPD4. Clinical phenotyping included audiological assessment and evaluation for neurodevelopmental involvement. Cross-species expression analyses were conducted in Drosophila, zebrafish, and mouse. Functional characterization included quantitative evaluation of sound-evoked responses in Drosophila nicht gut hoerend (ngh) mutants, assessment of neuronal development and acoustic startle responses in zebrafish loss of function models, and morphological cochlear analyses with auditory brainstem response measurements in knockout mice. Results Three affected males from two unrelated families presented with prelingual, bilaterally symmetrical sensorineural hearing loss, with confirmed congenital onset in one individual and no evidence of neurodevelopmental abnormalities. Cross-species analyses demonstrated evolutionarily conserved expression of FRMPD4 in auditory structures. In Drosophila, quantitative analysis of sound-evoked responses in ngh mutants revealed impaired auditory function. Zebrafish loss of function models exhibited reduced neuronal populations in the otic vesicle and posterior lateral line, abnormal neuromast development, and diminished acoustic startle responses. In mice, Frmpd4 knockout resulted in high-frequency hearing loss and cochlear abnormalities consistent with the human phenotype. Conclusions Our findings expand the phenotypic spectrum of FRMPD4 to include non-syndromic sensorineural hearing loss and establish its evolutionarily conserved role in auditory function. These results have direct implications for genetic diagnosis and variant interpretation in patients with hearing loss.

Purpose: Aicardi-Goutieres syndrome (AGS) is a type I interferonopathy presently associated with nine genes. PTPN1 is a negative regulator of the interferon pathway previously associated with chronic inflammation and recently type 1 IFN autoinflammation. Methods: Genomic data from undiagnosed individuals with suspected AGS were interrogated for PTPN1 variants, and predicted loss-of-function (pLOF) and damaging missense variants in PTPN1 were sought in two additional academic databases as well as the All of Us database. Results: We identified 13 cases with ultra-rare heterozygous pLOF or highly damaging missense variants in PTPN1. Nine cases were identified in a cohort of 53 individuals (~ 17%) with clinical, imaging and persistent biochemical features of AGS. Median age of onset is 1.75 years (IQR 0.67), significantly later (p< 0.0001) than other AGS genotypes. Four additional cases were identified in academic datasets with variable clinical features suggestive of autoinflammation. Additionally, 49 individuals with ultra-rare, damaging PTPN1 variants were identified in the All of Us database, none had features suggestive of AGS, but autoimmunity was highly prevalent (~21.6%). Conclusion: Our data implicate PTPN1 as a cause of later-onset presentations of AGS within a broader spectrum of autoinflammatory phenotypes. Segregation and biobank data demonstrate reduced penetrance, with carriers being enriched for autoimmune disorders.

Background: Palliative care services improve quality of life and health outcomes for individuals living with chronic and life-limiting illnesses. Although these services have expanded considerably in urban areas, their availability remains limited in many rural communities. This study aimed to identify key components of integrated palliative care services and examine how these elements are implemented within rural healthcare systems in southern Minnesota. Methods: A qualitative case study using deductive content analysis was conducted. Semi-structured interviews were carried out with healthcare professionals involved in palliative and hospice care serving rural communities in southern Minnesota. Results: Participants identified several essential components of integrated palliative care, including multidisciplinary care teams, continuity of care across healthcare settings, interprofessional collaboration, and early identification of patients who may benefit from palliative care. Existing services in southern Minnesota incorporate several integrated elements, such as coordinated care teams, individualized care plans, nurse-led case management, professional training, and the use of virtual visits for geographically distant patients. However, participants also identified important gaps, including limited availability of palliative care services in rural areas, fragmented continuity of care, challenges in early patient identification, funding and insurance barriers, and the absence of a unified palliative care network. Conclusions: While palliative care services in southern Minnesota demonstrate important strengths, further efforts are required to improve service integration, coordination, and access for rural populations. Strengthening integrated PCSs may help reduce disparities in access to care and improve service delivery for rural patients and their families. These findings may inform the development of integrated palliative care models in rural healthcare systems beyond the study setting.