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Background/Objectives: Steroid-induced glaucoma (SIG) or ocular hypertension is a well-known complication after corticosteroid exposure to the eye, particularly intravitreal dexamethasone implantation. The main mechanism of elevated intraocular pressure (IOP) is trabecular meshwork dysfunction, leading to increased aqueous outflow resistance. Although most SIG cases respond to medical treatment, some patients develop persistent IOP elevation, requiring surgical intervention. Minimally invasive glaucoma surgery (MIGS) has recently emerged as a safer surgical option, but there are a limited number of reports using MIGS for SIG. Methods: A 73-year-old man, who had branch retinal vein occlusion with refractory macular edema despite multiple anti-VEGF injections, received an intravitreal Ozurdex® (Allergan, Irvine, CA, USA) implant. He developed marked IOP elevation from 17 to 34 mmHg despite maximal topical therapy. Visual field progression and progressive retinal nerve fiber layer thinning were also observed. Given the need for continued ocular steroid use and only having one arm due to trauma making drops difficult, three trabecular micro-bypass stent devices (iStent infinite®, Glaukos Corp., Aliso Viejo, CA, USA) were implanted for IOP control. Postoperatively, IOP decreased to 13 mmHg and remained stable at 15 mmHg for 12 months. Additionally, macular edema was well-controlled with ongoing Ozurdex treatment and no observed IOP spikes. Conclusions: This is the first reported case of SIG-associated Ozurdex successfully managed with triple trabecular micro-bypass stents. The iStent infinite implantation provided safe and sustained IOP control for SIG, highlighting its potential role in patients requiring continuous intravitreal steroids.

Periprocedural thromboembolic events are common complications of neuroendovascular treatment. We aimed to determine the incidence and potential risk factors of DWI-positive lesions detected on postoperative MRI after Woven EndoBridge (MicroVention/Terumo, Aliso Viejo, CA, USA) treatment for intracranial aneurysms. Between February 2021 and April 2025, 55 patients underwent Woven EndoBridge treatment for 59 intracranial aneurysms at two neurovascular institutions in Japan. Of these, 37 patients with 40 unruptured intracranial aneurysms treated with the Woven EndoBridge device alone were retrospectively enrolled. The distal access catheter/parent artery ratio was defined as the outer diameter of the distal tip of the distal access catheter divided by the diameter of the parent artery. MRI was performed within 48 hours after the procedure to evaluate appearance and number of DWI-positive lesions. DWI-positive lesions after Woven EndoBridge treatment were confirmed in 28 (70.0%) unruptured intracranial aneurysms. Univariate analysis revealed a trend toward a higher proportion of age ≥70 years (DWI-positive lesion [-] group: 33.3% vs [+] group: 64.3%, P=.09). The proportion of distal access catheter/parent artery ratio ≥0.70 differed significantly between the two groups (DWI-positive lesion [-] group: 8.3% vs [+] group: 53.6%, P=.01). In the multiple logistic regression model using age and distal access catheter/parent artery ratio, a distal access catheter/parent artery ratio (OR, 111.00; 95% CI, 0.76-16000.00; P=.06) was identified as a marginally significant risk factor for postprocedural DWI-positive lesions. Furthermore, the eligible cases were divided into two groups: DWI-positive lesion ≥10 (-) group (n=31, 77.5%) and ≥10 (+) group (n=9, 22.5%). Univariate analysis revealed significant differences in the proportion of age ≥70 years (45.2% vs 88.9%, P=.03) and those with a distal access catheter/parent artery ratio ≥0.80 (9.7% vs 66.7%, P=.001). In the multiple logistic regression model using age and distal access catheter/parent artery ratio, a significant relationship was found between distal access catheter/parent artery ratio (OR, 1400.00; 95% CI, 3.70-533000.00; P=.02) and postprocedural DWI-positive lesion ≥10 following Woven EndoBridge treatment. Distal access catheter/parent artery ratio in Woven EndoBridge treatment may affect DWI-positive lesions incidence and postprocedural count.

To describe the feasibility of Woven EndoBridge (WEB; Terumo Neuro, Aliso Viejo, CA, USA) treatment for an aneurysm at the distal anterior cerebral artery A4 bifurcation and to highlight technical considerations for achieving peripheral access. A 57-year-old woman was incidentally diagnosed with an unruptured distal anterior cerebral artery aneurysm during a brain MRI performed for evaluation of headache. DSA demonstrated a wide-neck aneurysm arising at the A4 bifurcation of a right-dominant bihemispheric distal anterior cerebral artery (neck width, 5.90 mm; dome, 6.53 × 7.76 mm [mean, 7.15 mm]; height, 6.82 mm). Given the broad neck configuration and the necessity of preserving both distal branches, intrasaccular flow disruption using a WEB device was considered appropriate. Advancement through the A1 segment was impeded by steep angulation at the internal carotid artery-A1 junction and a pronounced ledge effect. The buddy-wire technique was initially attempted to improve support and trackability, but was unsuccessful. Stable access to the A2 segment was achieved only after catheter reshaping without further use of the buddy wire. A WEB SL 8 × 3 mm device (Terumo Neuro) was deployed, achieving adequate neck coverage with a marked reduction in aneurysmal inflow while maintaining patency of both distal anterior cerebral artery branches. The procedure was completed without any procedure-related complications. Follow-up MRI/MRA at 1 month showed no evidence of residual aneurysm filling and no branch-related complications. In selected distal anterior cerebral artery aneurysms where branch preservation is essential and parent-artery protrusion can be avoided, WEB treatment may be a useful endovascular option. This case illustrates the feasibility of WEB treatment of aneurysms at the anterior cerebral artery A4 bifurcation.

This Woven EndoBridge Database (W-EB DB) study was conducted using data from a nationwide, multicenter database to evaluate the safety and efficacy of the W-EB device (MicroVention, Aliso Viejo, CA, USA; distributed by Terumo, Tokyo, Japan) for the treatment of wide-neck intracranial bifurcation aneurysms in Japanese patients. In this paper, we confirm the clinical usefulness of the W-EB device in Japanese patients based on the comparable 1-year post-procedure outcomes to those reported from overseas. This W-EB DB study was a post-marketing, open-label, non-randomized cohort study conducted using the database of the Japanese Society of Neuroendovascular Therapy (JSNET). A total of 128 participants (including 103 patients with unruptured aneurysms and 25 patients with ruptured aneurysms) treated with the W-EB device between December 2020 and December 2025 at any of the 12 participating centers were included in this study. Clinical data collected from the database consisted of the patient demographics, comorbidities, aneurysm characteristics (location, size, and neck width), procedural details, and follow-up outcomes. The safety endpoints were the incidences of subarachnoid hemorrhage (SAH), rebleeding, cerebral infarction, and other adverse events occurring within 1 year after the procedure. The efficacy endpoints were the aneurysm occlusion rates and retreatment rates at 180 days and 1 year after the procedure; the aneurysm occlusion status was determined in accordance with the W-EB Occlusion Scale (WOS). We used descriptive statistics to analyze the results. The research within our submission was approved by the institutional ethics review board of Kyoto University (Approval No. R2088). In regard to the safety endpoints, SAH occurred in 1 patient (1.0%) with an unruptured aneurysm, and rebleeding occurred in 1 patient (4.0%) with a ruptured aneurysm. The incidence of cerebral infarction was 7.0%. Most other adverse events were mild, and no new device-related risks were identified. In regard to the efficacy of the device, at 1 year post-procedure, complete occlusion (WOS grade A or B) was achieved in 58 of 95 lesions (61.1%) and adequate occlusion (WOS grade A, B, or C) was achieved in 79 of 95 lesions (83.2%). Retreatment was needed for 5 of 126 lesions (4.0%). The safety and efficacy outcomes were comparable to those reported from multicenter studies conducted in Europe and the United States, with slightly higher complete occlusion rates and similar adequate occlusion and retreatment rates. Favorable safety and effectiveness of the W-EB device were observed at 1 year after device deployment in Japanese patients with wide-neck intracranial aneurysms. These findings are consistent with international reports and support the clinical utility of the W-EB device, given the low incidence of serious complications.

The CURRENT registry is a prospective, multicenter, real-world investigation designed to evaluate the safety and effectiveness of the Renzan™ stent (Terumo MicroVention Inc., Aliso Viejo, CA, USA) in patients with femoro-popliteal peripheral artery disease (PAD), including complex lesions and chronic limb-threatening ischemia (CLTI). This study reports the interim outcomes at 6 and 12 months. A total of 89 patients with symptomatic PAD (Rutherford category IV-V 64.1%) were enrolled across three centers in Tuscany, Italy. All patients underwent endovascular treatment with the Renzan™ dual-layer interwoven nitinol stent. Baseline and follow-up assessments included clinical evaluation and duplex ultrasound imaging. The primary safety endpoint was the composite rate of all-cause death, target lesion revascularization (TLR), and major amputation at 30 days. The primary efficacy endpoint was primary patency at 6 months. Estimated patency and reintervention rates were reported at 12 months using Kaplan-Meier analysis. Technical and procedural success was achieved in 100% of cases. At 30 days, no deaths, TLRs, or major amputations occurred. At 6 months, the composite safety endpoint was met in 94.3% of patients. Primary patency was 100% at 1 and 3 months, 92.0% at 6 months, and declined to 78.7% (95% CI: 55.3-88.1%) at 12 months. Freedom from TLR was 97.2% at 6 months and 78.5% (95% CI: 63.7-88.7%) at 12 months. Exploratory multivariable analysis identified diabetes mellitus, previous peripheral endovascular intervention, and below-the-knee involvement as independent predictors of loss of patency, whereas dual antiplatelet therapy beyond 1 months was associated with a reduced risk of patency loss. The Renzan™ stent demonstrated excellent early safety and efficacy outcomes in a challenging PAD population, with sustained mid-term patency despite a high proportion of complex lesions. These preliminary results support the use of this new mimetic stent design in real-world clinical settings and warrant further confirmation with longer-term follow-up.

This case report describes a rare mechanical etiology of postoperative refractive surprise - anterior displacement of an intraocular lens (IOL) secondary to localized posterior synechiae - in a patient with plateau iris syndrome (PIS) following combined clear lens extraction (CLE) and minimally invasive glaucoma surgery (MIGS). A 29-year-old man with PIS and medically refractory chronic angle-closure glaucoma underwent an uneventful left-eye CLE, goniosynechiolysis, implantation of a toric extended depth-of-focus (EDOF) IOL, and insertion of three iStent infinite® (Glaukos Corporation, Aliso Viejo, CA, USA) devices. Five weeks postoperatively, he presented with blurred vision, asthenopia, and binocular diplopia associated with a sudden -2.50 D myopic surprise. Dynamic slit-lamp examination revealed localized posterior synechiae extending from 1 to 5 o'clock. These adhesions exerted asymmetrical traction on the capsular bag, resulting in anterior displacement and temporal tilt of the IOL complex without pupillary block. The patient subsequently underwent targeted synechiolysis under local anesthesia. Postoperative biometry demonstrated an increase in anterior chamber depth (ACD) from 2.90 mm to 3.02 mm, confirming posterior repositioning of the IOL. Restoration of the effective lens position (ELP) reversed the myopic shift and resolved the patient's symptoms. This case highlights localized posterior synechiae as a rare but reversible cause of postoperative refractive surprise and underscores the importance of meticulous dynamic slit-lamp evaluation and ACD monitoring in patients with complex anterior segment conditions presenting with unexpected refractive outcomes. Timely synechiolysis may serve as a definitive and restorative intervention.

This study aimed to explore the safety and efficacy of sustained release bimatoprost implant with SpyGlass intraocular lens (SpyGlass Pharma, Inc., Aliso Viejo, CA, USA). Twenty-four subjects diagnosed with cataracts and mild-to-moderate primary open-angle glaucoma were consented at a single site in Honduras. Those with pathologies that could confound outcomes were excluded. All subjects were required to have responded to topical prostaglandin analogues. Medication washout was performed prior to intervention. One eye of each subject was sequentially assigned to one of three arms (75 μg, 150 μg, or 300 μg of bimatoprost pads). The product was delivered in-the-bag via a commercially available intraocular lens (IOL) inserter and did not modify the steps of standard phacoemulsification cataract surgery other than attachment of bimatoprost implants to the IOL. We report interim results through 36 months. Twenty-one of 24 enrollees (87.5%) were retained through 36 months. Through 24 months, all subjects achieved the primary endpoint of intraocular pressure (IOP) reduction > 20% from baseline without any additional glaucoma medications. By month 36, all but a single subject (95.2%, n = 20) remained drop-free with continued IOP reductions > 20% across all remaining subjects. Each treatment arm realized mean IOP reductions from 32.3% to 49.3% over 3 years of follow-up visits. There were no significant intergroup differences. All eyes had a final best-corrected distance visual acuity of 20/30 or better. There were no serious implant-related adverse events. The most common events were dry eye (21.7%), transient vision decrease (13.0%), and subconjunctival hemorrhage (8.7%). All implants remained in the capsular bag. The first human study of a novel system that mounts bimatoprost-infused pads to a single-piece IOL suggests favorable safety and efficacy and does not require additional surgical skills beyond routine cataract surgery. A larger sample with comparative data is necessary to further assess effects. ClinicalTrials.gov identifiers, NCT07154797 and NCT07154810. Retrospectively registered on September 3, 2025.

Pathologically, cholangiocarcinoma (CCA) can be classified into small duct type and large duct type. This study evaluated clinical and molecular features of CCA according to its pathological subtype. We analyzed 107 patients with CCA from three independent cohorts who underwent curative surgical resection. Clinical data, gene expression profiles, and mutation status were compared between pathological subtypes. Sixty four (59.8 %) and 43 (30.2 %) patients were categorized as small duct type and large duct type, respectively. The large duct type was significantly associated with N1 stage and higher preoperative serum CEA and CA 19-9 levels. Survival outcomes were significantly poorer in patients with large duct type CCA. Transcriptomic analysis identified 146 differentially expressed genes between the two subtypes, which were validated in an independent cohort. Pathway analysis demonstrated enrichment of inflammation-related and AKT/KRAS-associated signaling pathways in the large duct type. Mutation analysis showed that KRAS and PIK3CA mutations were more frequent in the large duct type, while IDH1/2 mutations and FGFR2 fusions were more common in the small duct type. Pathological subtypes of CCA exhibit distinct clinical outcomes and molecular characteristics. Classification based on pathological subtype provides a useful framework for understanding the clinical and molecular heterogeneity of CCA.

Obtaining a precise genetic tuberous sclerosis complex diagnosis is a challenge as many missense TSC2 variants are variants of uncertain significance. Variants of uncertain significance in TSC2 have been resolved by one-at-a-time functional assays, but these assays cannot scale to the 3634 TSC2 missense variants of uncertain significance observed so far. To address this challenge, we use massively parallel sequencing to measure the steady-state abundance of almost 9000 TSC2 missense variants and develop an mTOR pathway activity assay using genome editing and cell sorting to generate activity scores for 391 missense variants. We observe that 1256 of 8864 (14.17%) missense variants assayed have altered TSC2 abundance, and 69 of 391 (17.65%) missense variants assayed have altered mTOR pathway activity. Calibration and integration of these data into classification of variants identified in a clinical cohort putatively reclassifies 212 of 276 (76.8%) TSC2 missense variants of uncertain significance. These datasets will lead to improved genetic diagnosis of tuberous sclerosis complex with potential positive impacts on the clinical management of patients and their families.

Macrocephaly, defined as a large head size, has a very broad differential and sometimes can be challenging to differentiate as benign versus indicative of pathology. In this review, we outline a stepwise approach to improving diagnosis of neurogenetic disorders versus other causes using the example of PTEN (phosphatase and TENsin homolog) Hamartoma Tumor Syndrome (PHTS). PHTS is a multiple hamartoma syndrome with medical management implications including the need for tumor surveillance, but often cases are not diagnosed until later in adulthood. Our review emphasizes the utility of using head circumference z scores in combination with other features as a triage tool for genetic identification of disorders such as PHTS.

Although RNA analysis holds potential to increase the diagnostic yield of exome sequencing (ES) for rare disease, its practical utility and barriers to its large-scale implementation have not been well studied. To quantify the impact of RNA analysis in clinical ES, we retrospectively assessed variants reported over a nearly 5-year period at a single clinical laboratory. Reported variants and corresponding genes were assessed based on 4 eligibility criteria for RNA analysis at our laboratory: (1) suspected spliceogenic impact, (2) sufficient gene expression in blood, (3) characterized gene with at least moderate gene-disease validity, and (4) mechanism of disease is loss of function (LOF). A total of 1987 unique variants were reported on ES during the study period. In total, 11.4% (226/1987) were putative splicing variants, 68.2% (1355/1987) had sufficient gene expression in blood, 83.0% (1650/1987) were in a gene with a LOF mechanism, and 98.9% (1965/1987) occurred in characterized genes. When assessed on the 4 criteria combined, 7.6% (152/1987) of variants were eligible for RNA analysis. Of those variants, which were identified in 153 individuals, 35.5% (54/152) were variant of uncertain significance (VUS), representing 5.2% (54/1035) of all VUS reported. Nine cases were successfully recruited for retrospective RNA analyses, 7 of whom had VUS and 2 who had a likely pathogenic variant. Of the VUS, 71.4% (5/7) were upgraded, whereas 28.6% (2/7) remained a VUS. The 2 likely pathogenic variants remained likely pathogenic. These findings indicate that putative splicing variants represent a substantial portion of VUS in this clinical ES cohort, and most were identified in characterized LOF genes with RNA expression in blood. Integrating RNA analysis with clinical ES could clarify over 5% of reported VUS, even when accounting for known limitations in a rare disease setting, making it a viable strategy to increase diagnostic accuracy and the likelihood that a patient will receive a clinically meaningful report.

Surface modifications may improve procedural safety of flow diverter (FD) treatment, but larger studies are rare. This multicenter study aims to evaluate the safety and efficacy of unruptured aneurysm treatment with surface-modified and coated FDs. Patients treated with the following FDs at 8 neurovascular centers were retrospectively reviewed: Pipeline Vantage Embolization Device, Pipeline Flex with Shield Technology, FRED X, p48/64 HPC, Derivo Embolization Device (DED), and DED 2heal. Aneurysm characteristics, procedural details, and angiographic results were evaluated in detail. A total of 511 patients with 545 aneurysms were included (mean aneurysm size: 8.2 ± 5.5 mm, 12% posterior circulation, 14% non-saccular morphology). Multiple FDs were used in 26/515 (5%) procedures and adjunctive coiling in 76 (15%). Thromboembolic events occurred in 40 (7.8%) cases, including 9 (1.7%) major ischemic events, 20 (3.9%) minor ischemic events and 11 (2.1%) asymptomatic/technical events. Non-saccular aneurysm morphology (p = 0.014) and use of multiple FDs (p = 0.025) favored thromboembolic events. Hemorrhagic events occurred in 5 (1.0%) cases, of which 3 were symptomatic. The combined morbidity and mortality rate was 11/515 (2.1%). Complete and adequate occlusion rates were 66% (196/297) and 80% (238/297) at 6 months, respectively, and 70% (64/92) and 85% (78/92) at 12 months, respectively. The present study demonstrates high safety and efficacy for coated or surface-modified FDs. Whether the surface modifications confer a clinical benefit needs to be addressed in comparative studies.

Hereditary anemias are a cause of nonimmune hydrops fetalis (NIHF). Our objective was to review the spectrum of hereditary anemia genes in NIHF diagnosed by exome sequencing (ES). We performed a systematic review of ES studies in NIHF from January 1, 2000 to August 1, 2024 with emphasis on genes causing fetal anemia as a primary phenotype. Forty-one ES studies with 207 genetically diagnosed NIHF cases met our inclusion criteria; 6 cases within 6 studies involved NIHF and hereditary anemia. Among the six cases, five had definitive diagnosis or likely diagnosis supported by pathogenic or likely pathogenic variants, while one case harbored only variants of uncertain significance and was classified as a possible diagnosis. The six different hereditary anemia genes included SEC23B, SPTA1, KLF1, RPL11, UNC13D, and RFWD3. Overall, ES confirmed the etiology of hereditary anemia in 2.4% (5/207) of genetically diagnosed NIHF cases. Hereditary anemias, therefore, represent a distinct and clinically relevant subset of ES-diagnosed NIHF cases. ES should be considered first line in fetuses with NIHF, as common non-genetic causes such as fetomaternal hemorrhage, infectious etiologies, and alloimmunization are excluded. It is also indicated when fetal anemia is suspected, particularly in the setting of elevated MCA Dopplers with a negative evaluation for common hemoglobinopathies and nongenetic etiologies.

Over the past three decades, Hereditary Cancer Testing (HCT) has evolved from single gene assays into multigene panel testing (MGPT), which allows for the screening of all known hereditary cancer genes in a single assay. MGPT is currently the standard approach for clinical HCT. However, with decreasing sequencing costs and increased instrument throughput, the scalability of exome sequencing (ES) and genome sequencing (GS) for HCT indications is becoming more viable. These methods provide broader insights into the coding exons and/or the entire genome, respectively. ES/GS data can also be reanalyzed to identify variants in novel genes that were not characterized at the time of initial testing, or to support research efforts aimed at uncovering additional associations between germline variants and cancer predisposition. Additionally, the emerging use of long-read sequencing (LRS) is noteworthy, enabling improved variant detection compared to short-read sequencing, especially for complex/structural variants and variation in difficult-to-sequence or paralogous regions in genes such as PMS2. This has the potential to increase the accuracy of HCT, reduce the turnaround time, find previously unidentifiable cancer risk variants, and ultimately increase the diagnostic yield. This article provides a comprehensive summary of the sequencing approaches used in HCT, discussing their strengths and limitations. We also highlight the added value of complementing DNA-only testing with RNA and tumor sequencing. Furthermore, we explore LRS-based approaches and discuss opportunities for their implementation in routine genetic testing for hereditary cancer.

Transient neonatal zinc deficiency (TNZD) is a genetic condition that presents with dermatitis, alopecia, diarrhea, and growth faltering in breast milk-fed infants of females with a heterozygous pathogenic variant in SLC30A2, the primary zinc transporter in mammary glands. Despite being an easily treatable condition, effectively evaluating for TNZD can be challenging because the infant's genotype does not reliably reflect the mother's genotype. Herein, we present our approach to diagnosis in an exclusively breastfed 5-month-old infant with treatment-refractory eczematous rash, admitted for growth faltering and decreased serum zinc and alkaline phosphatase levels. The infant was diagnosed with TNZD via trio genome-based exome sequencing after a heterozygous SLC30A2 variant of uncertain significance (VUS) (c.927G>C; p.Trp309Cys) was identified in the proband's mother, which was notably absent in the proband. Breast milk zinc concentration ([Zn]) was measured in duplicate via inductively coupled mass spectrometry in 10 samples (3 from the proband's mother and 7 from unrelated controls) and measured -265, -144, and -46 μg/dL below expected [Zn] at 0, 5, and 7 months postpartum, respectively, compared to an average deviation of -29 μg/dL in controls. Zinc supplementation in the infant led to rapid clinical improvement. The absence of the maternal SLC30A2 variant in the proband underscores diagnostic challenges in evaluating for TNZD, as primary variant analysis is typically limited to the proband in trio testing. Though the prevalence of SLC30A2 disease-causing variants is unclear, carrier screening may provide a unique opportunity to proactively identify females with known pathogenic SLC30A2 variants that would impart risk to their future breastfed children and breast milk recipients.

Up to 80% of people with heart failure experience cognitive impairment, which is linked to reduced cardiac function and cerebral hypoperfusion, causing neuropsychological changes related to brain injury. To identify prevalent causes of heart failure-related cognitive impairment, synthesize literature on its indicators and mechanisms, discuss affected cognitive domains, and explore research and clinical implications. This narrative review included empirical studies of cognitive performance in individuals with heart failure. Included studies were written in English and used original data. Cognitive impairment in individuals with heart failure is associated with disease severity, reduced ejection fraction, and lower systolic blood pressure. Cerebral hypoperfusion, microembolic events, and brain abnormalities contribute to deficits in attention, memory, and executive function. Further research is needed to understand the relationship between cerebral hemodynamics and cognitive function, identify early decline markers, and optimize screening and management strategies. Integrating cognitive screening into routine care may improve outcomes for individuals with heart failure-related cognitive impairment.

Leukodystrophies are a clinically and genetically heterogeneous group of diseases characterized by white matter abnormalities on brain magnetic resonance imaging. Clinical, biochemical, molecular, and/or neuroimaging findings collectively support the diagnosis confirmation. The heterogeneous and overlapping clinical presentations of different leukodystrophies and non-diagnostic molecular testing pose a significant challenge to establishing a definitive diagnosis in these rare diseases. The Myelin Disorders Biorepository Project is an observational research program that aims to establish new tests to diagnose leukodystrophies and describe the natural history of these disorders. Ensuring an accurate diagnosis is critical to the goals of this project, and this paper aims to describe the rigorous diagnostic review and confirmation process which was developed. We present a diagnosis review process that contributes to an accurate diagnosis for participants enrolled in this study. Board-certified genetic counselors with expertise in these disorders audit medical records to carefully assess each enrolled participant's clinical, biochemical, and molecular features. A scale of diagnostic categories is assigned based on the record review, and a team of leukodystrophy physician experts consults for cases that require further characterization or clarification. This robust review process has resulted in a database of individuals with verified diagnoses that may be easily queried for inclusion in appropriate natural history studies and/or treatment trials. This is a model framework that may be adapted and implemented by other rare disease groups.

For many evidence criteria within v3.0 of the ACMG/AMP guidelines, methodologies have been developed to empower their use outside the stipulated evidence strengths. However, no such methodology has been established for case-control data (PS4). With the release of large-scale unselected case-control datasets and expansion of nationally-collected laboratory datasets enriched for pathogenic variant carriers, there is potential to combine datasets across ascertainment contexts in a more quantitative manner using novel likelihood ratio tools. Using our published PS4-LR-Calculator, we calculated a combined log likelihood ratio (PS4-LLR) across five datasets (three unselected, and two enriched), and estimated enrichment of pathogenic variants in clinically-ascertained laboratory data using truncating variant prevalence. Data were combined for 10,817 missense variants from 325,345 female breast cancer patients and 671,006 controls of Western European ancestry for five breast cancer susceptibility genes (BRCA1, BRCA2, PALB2, ATM, CHEK2). A combined LLR was produced for 4,690 missense variants; 927 variants received evidence towards pathogenicity (LLR≥ 1), and 3,242 received evidence towards benignity (LLR≤ -1). This flexible, variant-level methodology combines nationally-collected 'enriched' datasets with unselected case-control cohorts, expanding the available information for case-control analysis, boosting power, enabling exploration of atypical penetrance and empowering variant classification.

Rare disease research and diagnosis rely on the integration of genomic and phenotypic data generated across diverse clinical sites; however, the absence of widely adopted standards for representing genomic data and associated metadata has limited data interoperability, reuse, and cross-study analysis. The Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium was established to investigate challenging rare disease cases and evaluate emerging multi-omic technologies for clinical translation. To support coordinated data integration across distributed research sites, we developed a common Consortium Data Model in partnership with domain experts to standardize the capture of participant-, family-, phenotype- and assay-level metadata, with a particular emphasis on using a modular architecture to support linking of multiple data versions from multiple omic technologies to a single individual and attribution of a genetic finding to the specific technology used for its initial discovery. Adoption of the GREGoR Data Model has enabled continued generation and public release of a harmonized, analysis-ready Consortium Dataset. The most recent release includes phenotypic, family and multi-omic data from 12,292 participants in 5,029 families. Other rare disease data sharing efforts are beginning to adopt this data model which will facilitate cross consortium analyses and empower rare disease research. This work demonstrates that a collaborative, flexible, and scalable data model can enable large-scale rare disease research, facilitate cross-center data harmonization, and enable data interoperability.