Comparing ability and norm-referenced scores as clinical trial outcomes for neurodevelopmental disabilities: a simulation study

Journal of Neurodevelopmental Disorders, Journal Year: 2023, Volume and Issue: 15(1)

Published: Jan. 17, 2023

Abstract Background For genetic conditions associated with neurodevelopmental disorder (GCAND), developmental domains such as motor ability, thinking and learning, social abilities, communication are potential intervention targets. Performance on measures of concepts can be expressed using several types scores. Norm-referenced scores intended for the diagnostic context, allowing identification impairment relative to age-based expectations, exhibit dramatic floor effects when used in individuals more significant limitations. Person ability scores, which derived via Rasch analysis or item response theory, available many standardized tests measure within-person change. However, they have not been evaluated primary endpoints GCAND clinical trials. In this study, we simulated a series parallel-arm trials under chronological age conditions, compare empirically power type I error rate operationalizing test performance rather than norm-referenced Results Using Vineland Adaptive Behavior Scales example, demonstrated an advantage statistical over at extreme levels impairment. This was least partially driven by where less severe, outperformed but were similar. The closely approximated nominal 5% both Conclusion results simulation demonstrate substantial interpretative studies that will enroll participants high These expected generalize concepts, regardless etiology specific test. is even greater higher Vineland.

Language: Английский

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Narrowing the diagnostic gap: Genomes, episignatures, long-read sequencing, and health economic analyses in an exome-negative intellectual disability cohort

Genetics in Medicine, Journal Year: 2024, Volume and Issue: 26(5), P. 101076 - 101076

Published: Jan. 19, 2024

Language: Английский

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The Mendelian disorders of chromatin machinery: Harnessing metabolic pathways and therapies for treatment

Molecular Genetics and Metabolism, Journal Year: 2024, Volume and Issue: 142(1), P. 108360 - 108360

Published: Feb. 27, 2024

The Mendelian disorders of chromatin machinery (MDCMs) represent a distinct subgroup that present with neurodevelopmental disability. regulates gene expression by range mechanisms, including post-translational modification histones, responding to histone marks, and remodelling nucleosomes. Some the MDCMs impact on may have potential therapeutic interventions. Two treatment strategies are enhance intracellular pool metabolites can act as substrates for modifiers use medications inhibit or promote residues influence expression. In this article we discuss treatments modifications involving acetylation methylation. Genomic technologies facilitating earlier diagnosis many disorders, providing opportunities early from infancy. This has parallels how inborn errors metabolism been afforded newborn screening. Before promise be fulfilled, require greater understanding biochemical fingerprint these conditions, which provide supplement modifying enzymes. Importantly, metabolomic profile affected individuals also disorder-specific biomarkers will critical demonstrating efficacy treatment, response not able accurately assessed clinical measures.

Language: Английский

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Diversity and consequences of structural variation in the human genome

Nature Reviews Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 21, 2025

Language: Английский

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Global developmental delay: comparison of developmental profiles between gene-positive/suspicious positive and gene-negative cases

Pediatric Research, Journal Year: 2025, Volume and Issue: unknown

Published: April 30, 2025

Global developmental delay (GDD) is associated with genetic abnormalities; however, the specific clinical and features that should trigger testing remain unclear. In this study, we explored issue. A total of 126 children GDD were recruited for study. Comprehensive medical histories physical examination data collected all participants. The Chinese adaptation Griffiths Mental Development Scales was used to assess neurodevelopmental outcomes. Genetic variations analyzed through trio-based whole exome sequencing proband genome sequencing. comparative analysis characteristics conducted between gene-positive/suspicious positive results (i.e., mutation deleterious or potentially deleterious, inheritance pattern phenotype are matched) those negative results. positive/suspicious rate genes 46.8%. locomotor, performance, general quotients lower in group than gene-negative (p < 0.05), locomotor ability, higher gene 0.05). Children abnormalities exhibited poorer compared without mutations. Furthermore, individuals ability be prioritized testing. This study aimed compare profiles who test suspiciously negative, identify key may serve as indicators It highlights Individuals findings supplement existing literature by providing insights guide clinicians on determining which considered

Language: Английский

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Improved Diagnostic Yield in Recessive Intellectual Disability Utilizing Systematic Whole Exome Sequencing Data Reanalysis

Clinical Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

ABSTRACT Recent advances in next generation sequencing (NGS) have positioned whole exome (WES) as an efficient first‐tier method genetic diagnosis. However, despite the diagnostic yield of 35%–50% intellectual disability (ID) many patients still remain undiagnosed due to inherent limitations and bioinformatic short‐comings. In this study, we reanalyzed WES data from 159 Iranian families showing recessively inherited ID. The reanalysis was conducted with initial clinical re‐evaluation their families, followed by using two updated pipelines. first phase, BWA‐GATK pipeline utilized for alignment variant calling, subsequent annotation ANNOVAR tool. This approach yielded causative variants 17 (10.6%). Among these, six genes ( MAZ, ACTR5, AKTIP, MIX23, SERPINB12, CDC25B ) were identified novel candidates potentially associated ID, supported bioinformatics functional segregation analysis. second negative results reassessed Illumina DRAGEN Bio‐IT platform variant‐calling, Ilyome, a newly developed web‐based tool, annotation. phase likely pathogenic additional increasing total 11.9% which is consistent other studies on cohorts conclusion, identification co‐segregating candidate emphasizes once more potential uncover previously unknown gene‐disease associations. Notably, it demonstrates that systematic tools thorough review literature new associations while performing phenotypic re‐evaluation, can improve outcome Consequently, if performed within 1–3 year period, reduce number cases may require costly methods such genome sequencing.

Language: Английский

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Exploring the connection between RNA splicing and intellectual disability

Current Opinion in Genetics & Development, Journal Year: 2025, Volume and Issue: 91, P. 102322 - 102322

Published: Feb. 8, 2025

Intellectual disability (ID) is a broad diagnostic category that encompasses individuals with impaired cognitive ability. While these disorders have heterogeneous causes, recent developments in next-generation sequencing (NGS) are revealing the prevalence of genetic etiologies. In particular, germline mutations genes affect RNA splicing increasingly common causes ID disorders. Research to elucidate functional relationship between and neurodevelopment critical since molecular therapeutics require nuanced understanding pathological mechanism. this review, we first summarize trends led discovery splicing-ID relationship, then discuss progress future directions for research surrounding neurodevelopment. Finally, speak on how results may serve as foundation burgeoning therapies.

Language: Английский

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‘Mind the Gap’—A Survey on Care Gaps and Priorities for the Transition to Adult Healthcare According to Caregivers of Young People With Rare Conditions Associated With Intellectual Disability

Journal of Intellectual Disability Research, Journal Year: 2025, Volume and Issue: unknown

Published: March 14, 2025

ABSTRACT Background For young people with rare conditions associated intellectual disability, the transfer from paediatric to adult healthcare providers is often complicated. European Reference Network ERN‐ITHACA (Intellectual TeleHealth, Autism and Congenital Anomalies) on Rare Malformations Intellectual Disability aims develop a clinical practice guideline improve this transition. The aim of study was identify which aspects transition care matter most describe current gap as experienced by caregivers inform scope. Methods An international web‐based survey conducted in January–February 2023. Priorities for good process gaps Europe were identified using ‘Mind Gap’ scale. surveys created plain easy‐to‐read language available nine languages. Results One hundred fifty‐seven 15 countries completed survey, representing over 40 conditions, including Phelan–McDermid, Rubinstein–Taybi, 22q11.2 deletion Kleefstra syndromes. Care identified, particularly related issues such preparation adaptation healthcare, supporting independence planning future. Items considered essential optimal individualised approaches, information provision coordination care. Discussion Coordinated, specialised, multidisciplinary required support youth disability transitional age. Supporting people's independence, orchestrating ensuring effective communication are challenging population.

Language: Английский

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Novel Compound Heterozygous Variants in ZNF526 Causing Dentici‐Novelli Neurodevelopmental Syndrome: A Case Report and Literature Review

Molecular Genetics & Genomic Medicine, Journal Year: 2025, Volume and Issue: 13(4)

Published: April 1, 2025

ABSTRACT Background The ZNF526 gene encodes a ubiquitously expressed Kruppel‐type zinc finger protein crucial in transcriptional regulation. Recent studies suggest that biallelic pathogenic variants may lead to Dentici‐Novelli neurodevelopmental syndrome, characterized by microcephaly, developmental delay, epilepsy, and ocular anomalies. To date, phenotypic details have been reported for only six patients with variants. Methods This study gathered clinical information genetic data from child disorders. A three‐dimensional model was employed predict variant effects on structure. literature review conducted compare this case previously cases, analyzing features findings. Results proband, 7‐month‐old girl, exhibited limb hypotonia, abnormal brain imaging, seizures. Chromosomal karyotype analysis copy number variation analyses were normal. Whole exome sequencing revealed two heterozygous the (NM_133444.3): c.1426del (p.Val476Phefs*9), de novo frameshift variant, c.1513T;> C (p.Cys505Arg), inherited her mother. These unreported are separate alleles, forming compound state correlated presentation. Ocular anomalies absent, while café‐au‐lait spots represent novel feature. Among 12 cases of 11 unique identified, loss‐of‐function possibly linked Conclusion describes youngest patient broadening mutation spectrum detailing associated profile. findings valuable diagnosis family counseling syndrome.

Language: Английский

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Protein-truncating variants and deletions of SHANK2 are associated with autism spectrum disorder and other neurodevelopmental concerns

Journal of Neurodevelopmental Disorders, Journal Year: 2025, Volume and Issue: 17(1)

Published: April 30, 2025

Language: Английский

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