Enhanced detection and genotyping of disease-associated tandem repeats using HMMSTR and targeted long-read sequencing DOI Creative Commons
Kinsey Van Deynze, Camille Mumm, Connor J. Maltby

и другие.

Nucleic Acids Research, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 20, 2024

Tandem repeat sequences comprise approximately 8% of the human genome and are linked to more than 50 neurodegenerative disorders. Accurate characterization disease-associated loci remains resource intensive often lacks high resolution genotype calls. We introduce a multiplexed, targeted nanopore sequencing panel HMMSTR, sequence-based tandem copy number caller which outperforms current signal- callers relative two assemblies we show it performs with accuracy in heterozygous regions at low read coverage. The flexible allows us capture disease associated an average coverage >150x. Using these tools, successfully characterize known or suspected expansions patient derived samples. In samples, also identify unexpected expanded alleles not previously underlying diagnosis. This genotyping approach for is scalable, simple, accurate, offering significant potential diagnostic applications investigation expansion co-occurrence

Язык: Английский

The molecular landscape of hereditary ataxia: a single-center study DOI Creative Commons

Elisa Bregant,

Elena Betto,

Chiara Dal Secco

и другие.

Human Genetics, Год журнала: 2025, Номер unknown

Опубликована: Апрель 10, 2025

Язык: Английский

Процитировано

0
Heterozygous and HomozygousRFC1 AAGGGRepeat Expansions are Common in Idiopathic Peripheral Neuropathy DOI
Zitian Tang, Sinem Ovunc,

Elle Mehinovic

и другие.

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Апрель 22, 2025

Biallelic intronic AAGGG repeat expansions in RFC1 cause Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome may also contribute to isolated sensory neuropathy. The clinical significance of both heterozygous biallelic more diverse patient populations remains unclear-partly due the absence accurate, user-friendly computational tools specifically tailored for tandem analysis. To discern relationship between idiopathic peripheral neuropathy (iPN), we performed whole-genome sequencing (WGS) followed by PCR-based confirmation a large, well-characterized U.S. cohort consisting 788 iPN patients (369 pure small fiber (SFN), 266 sensorimotor, 144 sensory, 9 motor). We developed an integrative pipeline combining ExpansionHunter Denovo Expansion Hunter coupled unsupervised clustering reliably detect genotype from short-read WGS data, achieving 98.2% concordance repeat-primed PCR based validation. were absent 879 controls but present 2.8% (Fisher's exact p = 5.9×10 -8 ), including 6.2% 2.2% SFN, 1.5% sensorimotor neuropathy, indicating that motor nerve involvement should not exclude screening. observed markedly increased frequency monoallelic compared (13.2% versus 2.5%; Fisher's 3.4×10 -17 without evidence secondary mutations or on other allele. Our approach provides robust, cost-effective method detecting data. findings indicate homozygous can development iPN.

Язык: Английский

Процитировано

0
Structural polymorphism of the nucleic acids in pentanucleotide repeats associated with the neurological disorder CANVAS DOI Creative Commons
Kenta Kudo, K Hori, Sefan Asamitsu

и другие.

Journal of Biological Chemistry, Год журнала: 2024, Номер 300(4), С. 107138 - 107138

Опубликована: Март 5, 2024

Short tandem repeats are inherently unstable during DNA replication depending on repeat length, and the expansion of length in human genome is responsible for disorders. Pentanucleotide AAGGG ACAGG expansions intron 2 gene encoding factor C subunit 1 (RFC1) cause cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) other phenotypes late-onset ataxia. Herein, we reveal structural polymorphism RFC1 associated with CANVAS vitro. Single-stranded formed a hybrid-type G-quadruplex, whereas its RNA parallel-type G-quadruplex three layers. The hairpin structure comprising C-G G-C base pairs A:A GA:AG mismatched repeats. Furthermore, both pathogenic RNAs more rigid structures than those non-pathogenic RNAs. These findings provide novel insights into repeats, which may be closely related to disease mechanism CANVAS.

Язык: Английский

Процитировано

2
Elucidating the pathobiology of Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome (CANVAS) with its expanded RNA structure formation and proteinopathy DOI Creative Commons
Krishna Singh, Sakshi Shukla, Uma Shankar

и другие.

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Ноя. 14, 2024

Numerous neurological disorders are linked to sequences rich in guanine repeats found introns, exons, and regulatory regions of genes. These have been observed form stable G-quadruplex (GQ) structures both vitro vitro. Cerebellar Ataxia with Neuropathy Vestibular Areflexia Syndrome (CANVAS), a slowly progressive neurodegenerative disorder, is associated the biallelic expansion (AAGGG)n pathogenic second intron RFC1 gene. Though these G-rich other diseases protein loss function, RNA gain and/or not much known about pathological mechanism CANVAS. Herein, we report formation GQ conformations CANVAS-associated i.e., r(AAGGG)n, where 'r' stands for RNA. GQs critical regulators leading foci binding sequestration. They also alter causative processes like retention, which leads us hypothesize toxic Proteinopathy Various biophysical biomolecular assays characterized interactions three aggregation-prone RNA-binding proteins (RBPs): heterogeneous nuclear ribonucleoprotein H1/F (hnRNP H1/F), DGCR8 different [(AAGGG)9] vitro, further affirming hypothesis. The observations supported by molecular dynamics analysis cell-based studies, putting step closer elucidating mechanism(s) CANVAS neuropathy, paving way development innovative therapeutic interventions.

Язык: Английский

Процитировано

1
What Are the Central Mechanisms of Cough and Their Neurologic Implications? DOI
Reece M. Hass, Eduardo E. Benarroch

Neurology, Год журнала: 2024, Номер 103(10)

Опубликована: Ноя. 7, 2024

Язык: Английский

Процитировано

0
Enhanced detection and genotyping of disease-associated tandem repeats using HMMSTR and targeted long-read sequencing DOI Creative Commons
Kinsey Van Deynze, Camille Mumm, Connor J. Maltby

и другие.

Nucleic Acids Research, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 20, 2024

Tandem repeat sequences comprise approximately 8% of the human genome and are linked to more than 50 neurodegenerative disorders. Accurate characterization disease-associated loci remains resource intensive often lacks high resolution genotype calls. We introduce a multiplexed, targeted nanopore sequencing panel HMMSTR, sequence-based tandem copy number caller which outperforms current signal- callers relative two assemblies we show it performs with accuracy in heterozygous regions at low read coverage. The flexible allows us capture disease associated an average coverage >150x. Using these tools, successfully characterize known or suspected expansions patient derived samples. In samples, also identify unexpected expanded alleles not previously underlying diagnosis. This genotyping approach for is scalable, simple, accurate, offering significant potential diagnostic applications investigation expansion co-occurrence

Язык: Английский

Процитировано

0