Jul 2026· Movement Disorders· 0 citations· 27 references
Medicine
TL;DR
The findings underscore the diagnostic potential of integrated long-read and multi-omic approaches for complex structural variant characterization, while illustrating persistent limitations of automated pipelines and highlighting unpredictable relationships between genomic, transcriptomic, and proteomic findings.
Abstract
Background
Long-read sequencing and multi-omic analytical frameworks are increasingly being adopted in rare disease diagnostics. However, clinical workflows comprehensively integrating these methodologies remain uncommon.
Objective
This study aimed to assess the potential and limitations of integrating long-read genomic, transcriptomic, and proteomic analyses to characterize complex structural variants.
Methods
Two unrelated patients presenting with dystonia and comorbid neurological features underwent nanopore-based long-read DNA sequencing. In patient 1, complementary transcriptomic and proteomic analyses were performed.
Results
The workflow enabled the identification and characterization of two pathogenic complex structural variants: a homozygous AluY-mediated inversion disrupting PANK2, underlying neurodegeneration with brain iron accumulation (patient 1), and a heterozygous de novo 16p13.3 duplication-triplication event associated with an atypical dystonia-parkinsonism phenotype (patient 2).
In FTD and ALS, these results support universal access to genetic testing independent of age at onset or family history, and provide a clear diagnostic advantage in NDDs marked by substantial clinical and genetic overlap.
Emma Ehn, H. Thonberg, Inger Nennesmo et al.· Human Molecular Genetics· 0 citations
Background Intellectual disabilities (IDs) are part of neurodevelopmental disorders (NDDs) and are genetically heterogeneous conditions characterized by impairments in cognition, learning, and adaptive functioning. Despite advances in gene discovery, many individuals, particularly those from understudied populations, remain without a molecular diagnosis. Recent reports implicate CCDC82 (HGNC: 26282) as an autosomal recessive ID gene, although the phenotypic spectrum and biological context remain incompletely defined. Methods Exome sequencing (ES) was performed in a consanguineous Pakistani family (PKMR06A) with four affected individuals presenting with moderate to severe ID. Variant segregation was confirmed by Sanger sequencing. In silico analyses, including pathogenicity prediction, protein structural modeling, and domain intolerance assessment, were used to evaluate the functional consequences of the identified variant. Spatiotemporal gene expression patterns were examined using bulk and single-cell human brain transcriptomic datasets. Results Clinically, affected individuals of family PKMR06A presented with early childhood global developmental delay, speech delay, hypotonia, gait abnormalities, spasticity, and mild facial dysmorphism. Genetic screening revealed a recurrent rare homozygous frameshift variant in CCDC82 (NM_024725.4): c.373del; p.(Asp125Ilefs*6), segregating with disease in all available affected individuals of the family. The identified c.373del variant was absent from the gnomAD database and was classified as pathogenic (PVS1, PM2, and PP1) based on ACMG/AMP criteria. The c.373del variant is predicted to introduce a premature termination codon, p.(Asp125Ilefs*6), leading to deletion of essential coiled-coil domains from the encoded protein, supporting a loss-of-function mechanism. In silico, transcriptomic analyses demonstrated preferential CCDC82 expression during prenatal human brain development, providing developmental context for the neurodevelopmental phenotype associated with the identified truncating variant. Conclusions This study expands the mutational landscape of CCDC82 and provides additional clinical and molecular evidence supporting its role in autosomal recessive NDD. The findings reinforce the importance of CCDC82 in human neurodevelopment and highlight the value of genomic investigation in underrepresented populations.
Tehmeena Akhter, S. Khan, Ahmed Abdul Mumeen et al.· Biochemistry and Biophysics...· 0 citations
The human brain is a genomic mosaic, where postzygotic mutations arising from embryogenesis to senescence drive diverse neurodevelopmental and neurodegenerative diseases. Because of numerous sequencing artifacts at ultralow variant allele frequencies (VAFs), detecting these variants remains a significant analytical challenge. This review focuses on single-nucleotide variants and small indels, summarizing current strategies for aligning sampling methods, including bulk, laser capture microdissection, and single-cell genomics, with the expected clonal architecture of the brain. It emphasizes that mosaic detection sensitivity is fundamentally constrained by sequencing depth, since even the most advanced algorithms cannot identify variants not physically represented in the sequencing library. The review further recommends the selection of variant calling algorithms based on validated VAF detection performance, matching tools like MuTect2 and MosaicForecast to their optimal performance ranges. Furthermore, we discuss how multitissue sampling, as emphasized by the SMaHT project, addresses the matched-control dilemma and supports accurate variant classification via cross-tissue VAF gradients. Integrating these established pipelines with multiomics modalities, including transcriptomic and epigenetic data, could advance the field toward a functional understanding of how the somatic genome impacts human brain health and disease.
Seungseok Kang, Yujin Oh, Sangwoo Kim· Current Opinion in Genetics...· 0 citations
Many neurological disorders (NDs) have a genetic basis, yet traditional diagnostic tools such as EEGs, EMGs, and neuroimaging primarily capture downstream manifestations. Although short-read sequencing (SRS) has advanced genetic diagnostics, significant gaps remain. Large repeat expansions, complex structural variants, mitochondrial variants, transcript splicing alterations, and epigenetic changes, all common contributors to NDs, are difficult to resolve with SRS. This review examines the capabilities of long-read sequencing (LRS) technologies in addressing these limitations. We evaluate studies leveraging LRS for genetic diagnosis in NDs and assess current barriers to clinical adoption, including technological, analytical, cost-related, and ethical considerations. By producing read lengths of tens of kilobases or more, LRS enables detection of variant types often inaccessible to SRS. Recent work has demonstrated its power in conditions such as Duchenne muscular dystrophy, fragile X syndrome, spinocerebellar ataxias, and unresolved mitochondrial syndromes. These findings highlight the potential of LRS to substantially increase diagnostic yield in NDs. However, major challenges persist: the need for high-quality DNA, demanding analytic pipelines, limited access outside major research centers, high costs, and ethical concerns including equity and management of incidental findings. LRS offers advantages for identifying complex genomic contributors to NDs and holds promise for improving diagnostic accuracy. Nonetheless, key technical, logistical, and ethical barriers must be addressed before widespread implementation is feasible. This review outlines current strengths, limitations, and emerging applications of LRS to guide clinicians and researchers in understanding how the technology can be applied today and what is needed for broader adoption.
Hanabi Geiger, Yutaka Furuta, B. L. Perera et al.· Neurological Sciences· 0 citations
ABSTRACT Introduction Autism spectrum disorder (ASD) is a neurodevelopmental condition with substantial genetic and phenotypic heterogeneity. However, populations of African ancestry remain underrepresented in genomic studies, limiting understanding of ASD genetic architecture. This study aimed to characterize rare, clinically relevant genetic variants in a Rwandan pediatric ASD cohort using trio‐based whole‐exome sequencing (WES). Methods Trio‐based WES was performed in 31 Rwandan pediatric patients with ASD (aged 2–18 years) and their parents. Variants were analyzed using a trio‐based workflow and classified according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines. Results Eleven candidate variants were identified in 9 of 31 patients, including four likely pathogenic variants and seven variants of uncertain significance. This resulted in a diagnostic yield of 12.9% (4/31), expanded to 29.0% when phenotypically concordant variants of uncertain significance were considered. Most likely pathogenic variants were identified in individuals with syndromic ASD who presented with intellectual disability, epilepsy, and global developmental delay. Likely pathogenic findings included two single nucleotide variants in GABRB3, SYNGAP1, and two copy‐number variants involving the GNAS locus and chromosome 1p35.3‐p35.2. Conclusions The diagnostic yield observed in this cohort is consistent with previous trio‐based WES studies of ASD. The findings support the clinical utility of WES for the genetic evaluation of ASD and underscore the need for expanded genomic studies in African populations.
Olivier Hakizimana, J. Hitayezu, J. P. Uyisenga et al.· Molecular Genetics & Genomic...· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
