The Brain Gene Registry: a data snapshot

Journal of Neurodevelopmental Disorders, Journal Year: 2024, Volume and Issue: 16(1)

Published: April 17, 2024

Abstract Monogenic disorders account for a large proportion of population-attributable risk neurodevelopmental disabilities. However, the data necessary to infer causal relationship between given genetic variant and particular disorder is often lacking. Recognizing this scientific roadblock, 13 Intellectual Developmental Disabilities Research Centers (IDDRCs) formed consortium create Brain Gene Registry (BGR), repository pairing clinical with phenotypic from participants variants in putative brain genes. Phenotypic profiles are assembled electronic health record (EHR) battery remotely administered standardized assessments collectively referred as Rapid Neurobehavioral Assessment Protocol (RNAP), which include cognitive, neurologic, neuropsychiatric assessments, well attention deficit hyperactivity (ADHD) autism spectrum (ASD). Co-enrollment BGR Clinical Genome Resource’s (ClinGen’s) GenomeConnect enables display information ClinVar. The currently contains on 479 who 55% male, 6% Asian, Black or African American, 76% white, 12% Hispanic/Latine. Over 200 genes represented BGR, 12 more harboring each these genes: CACNA1A, DNMT3A, SLC6A1, SETD5 , MYT1L. More than 30% de novo 43% classified uncertain significance (VUSs). Mean standard scores cognitive developmental screens below average cohort. EHR reveal delay earliest most common diagnosis sample, followed by speech language disorders, ASD, ADHD. has already been used accelerate gene-disease validity curation 36 evaluated ClinGen’s Disability (ID)-Autism (ASD) Curation Expert Panel. In summary, resource use stakeholders interested advancing translational research continues recruit clinically reported establish rich well-characterized national promote disorders.

Language: Английский

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Variant Reclassification in Underrepresented Minority Children With Sensorineural Hearing Loss

Ear and Hearing, Journal Year: 2025, Volume and Issue: unknown

Published: March 12, 2025

Objectives: Underrepresented minority (URM, comprising Hispanic, non-Hispanic Black, and Native American) children with sensorineural hearing loss have fivefold lower odds of receiving a genetic diagnosis after undergoing gene-panel testing. Using loss-specific American College Medical Genetics (ACMG)/Association for Molecular Pathology (AMP) guidelines applied to URM-specific cohort demonstrates the utility these in reducing disparity diagnostic efficacy testing URM populations. Design: A total 2740 variants from 715 patients (1275 348 patients) were queried. ACMG variant interpretation expert specification used attempt reclassification multihit (≥2 occurrences) uncertain significances (VUSs), focusing on case-control analysis relative ancestry-matched controls computational prediction. Results: Before curation, only 198 1275 (15.52%) population classified as likely pathogenic. Sixty-one VUSs, including OTOG , TJP2 COL11A2 34 other genes, probed using ACMG/AMP guidelines, resulting 19 variants. For remaining 42 would require parental segregation analysis. In addition VUSs that appeared at least twice our dataset, many additional once, but extremely rare or absent databases could be reclassified information. Conclusions: This study application HL-specific classification specifically dramatic effects it can clarifying pathogenicity thus contributing clinicians’ ability improve standard care improved accuracy subsequent early intervention.

Language: Английский

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Remote EEG Acquisition in Angelman Syndrome using PANDABox-EEG

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: April 3, 2025

Objective: We describe the development and validation of PANDABox-EEG, a novel protocol for remote EEG assessment with no on-site technician, tailored Angelman syndrome (AS). argue that this is reliable, valid, widely acceptable use in families affected by syndrome. Background: AS rare neurogenetic condition characterized developmental delays, sleep problems, seizures, happy demeanor. People are frequently monitored via to inform clinical care, EEG-measured delta activity has been proposed as reliable biomarker monitor treatment effectiveness. Traditional assessments pose logistical financial burdens due need travel medical center complete assessments. Telehealth methods, however, offer pathway forward. Methods: PANDABox-EEG was developed through multidisciplinary collaboration psychologists, psychophysiologists, engineers, special-education scholars, incorporating caregiver feedback user-centered design principles. It pairs PANDABox, telehealth platform biobehavioral disorders, ANT Neuro dry electrode system. Twenty-eight participants (7 AS, 7 siblings, 14 caregivers) completed three 5-minute sessions each over course week. Caregivers were asked provide on acceptability design, data quantified assessed metrics reliability validity. Results: demonstrated high feasibility acceptability, 91% caregivers reporting strong satisfaction comfort. quality promising, internal consistency (split-half range children AS: r= .96-.98) test-retest power among (test-retest ρ = .88-.96). Finally, we successfully detected characteristic increased (effect size between non-AS siblings: d=1.56-2.85) its association age siblings caregivers: d=2.19-2.72). Conclusion: provides feasible, cost-effective, method AS. Its ability capture relevant neurophysiological markers suggest potential broader application. With further validation, can enhance accessibility inclusivity, benefiting management research other populations frequent monitoring eliminating travel.

Language: Английский

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Increasing Diversity, Equity, Inclusion, and Accessibility in Rare Disease Clinical Trials

Pharmaceutical Medicine, Journal Year: 2024, Volume and Issue: 38(4), P. 261 - 276

Published: July 1, 2024

Language: Английский

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Hospital-wide access to genomic data advanced pediatric rare disease research and clinical outcomes

npj Genomic Medicine, Journal Year: 2024, Volume and Issue: 9(1)

Published: Dec. 2, 2024

Abstract Boston Children’s Hospital has established a genomic sequencing and analysis research initiative to improve clinical care for pediatric rare disease patients. Through the Rare Disease Collaborative (CRDC), hospital offers CLIA-grade exome genome sequencing, along with other types, patients enrolled in specialized studies. The data, consented broad use, are harmonized analyzed CRDC-supported variant interpretation tools. Since its launch, 66 investigators representing 26 divisions 45 phenotype-based cohorts have joined CRDC. These studies 4653 families, 35% of cases having finding either confirmed or under further investigation. This accessible genomics platform also supports additional institutional data collections, clinical, now encompasses 13,800+ their families. fostered new projects collaborations, increased genetic diagnoses accelerated innovative via integration care.

Language: Английский

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Survey of the Landscape of Society Practice Guidelines for Genetic Testing of Neurodevelopmental Disorders

Annals of Neurology, Journal Year: 2024, Volume and Issue: 96(5), P. 900 - 913

Published: Sept. 25, 2024

Genetic testing of patients with neurodevelopmental disabilities (NDDs) is critical for diagnosis, medical management, and access to precision therapies. Because genetic approaches evolve rapidly, professional society practice guidelines serve an essential role in guiding clinical care; however, several challenges exist regarding the creation equitable implementation these guidelines. In this scoping review, we assessed current state United States societies' pertaining unexplained global developmental delay, intellectual disability, autism spectrum disorder, cerebral palsy. We describe identified shortcomings argue need a unified, frequently updated, easily‐accessible cross‐specialty guideline. ANN NEUROL 2024;96:900–913

Language: Английский

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Where the Genetic Code Meets the Zip Code: Advancing Equity in Rare Disease Genomics

The Hastings Center Report, Journal Year: 2024, Volume and Issue: 54(S2)

Published: Dec. 1, 2024

Abstract The promise of genomic medicine lies in the opportunity to improve health outcomes via a personalized approach management, grounded genetic and variation unique an individual. However, disparities inequities mar this remarkable landscape innovation. Prior efforts understand these have focused on populations for which testing is relatively protocolized or where test utility varies greatly by ancestry groups, equitable are more clearly defined. We therefore consider current rare disease genomics, diagnostic approaches vary widely remains be fully understood, suggest path forward: how ecosocial theory may used guide novel equity‐focused initiatives that incorporate illness narratives population health. present examples narrative reimagine role discipline play sequencing studies, toward incorporation into clinical genetics genomics practice. Approaches broaden definitions interest will force field grapple with its racist history begin advance equity promote justice so truly deliver promise.

Language: Английский

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Utility of Genome Sequencing After Nondiagnostic Exome Sequencing in Unexplained Pediatric Epilepsy

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 9, 2024

Abstract Importance Epilepsy is the most common neurological disorder of childhood. Identifying genetic diagnoses underlying epilepsy critical to developing effective therapies and improving outcomes. Most children with non-acquired (unexplained) remain genetically unsolved, utility genome sequencing after nondiagnostic exome unknown. Objective To determine diagnostic (primary) clinical (secondary) in individuals unexplained pediatric epilepsy. Design This cohort study performed comprehensive analyses for 125 participants available biological parents enrolled from August 2018 May 2023, data analysis through April 2024 return likely findings. Clinical was evaluated. Setting Pediatric referral center Participants previous sequencing; when Exposure(s) Short-read Main Outcome(s) Measure(s) Primary outcome measures were yield sequencing, defined as percentage receiving a or finding, unique finding that required sequencing. The secondary measure impact on evaluation, treatment, prognosis participant their family. Results (58 [46%] female) median age at seizure onset 3 [IQR 1.25, 8] years, including 44 (35%) developmental epileptic encephalopathies. 7.2% (9/125), findings five cases four cases. Among solved cases, 7/9 (78%) variant detection (small copy number variant, three noncoding variants, difficult sequence small coding variants), 5.6% (7/125). documented 4/9 (44%). Conclusions Relevance These suggest can have should be considered patients Key Points Question What epilepsy? Findings In this identified Of nine seven solve, had utility. Meaning Genome identify not detectable by epilepsy, first-line testing

Language: Английский

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Survey of the Landscape of Society Practice Guidelines for Genetic Testing of Neurodevelopmental Disorders

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 23, 2024

ABSTRACT Genetic testing of patients with neurodevelopmental disabilities (NDDs) is critical for diagnosis, medical management, and access to precision therapies. Because genetic approaches evolve rapidly, professional society practice guidelines serve an essential role in guiding clinical care; however, several challenges exist regarding the creation equitable implementation these guidelines. In this scoping review, we assessed current state United States societies’ pertaining unexplained global developmental delay, intellectual disability, autism spectrum disorder, cerebral palsy. We describe identified shortcomings argue need a unified, frequently-updated easily-accessible cross-specialty guideline.

Language: Английский

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