Browse
Submit Data
Databases
API
Help

Dataset Information

28 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Longer CAG repeat length is associated with shorter survival after disease onset in Huntington disease.

ABSTRACT: It is well known that the length of the CAG trinucleotide expansion of the huntingtin gene is associated with many aspects of Huntington disease progression. These include age of clinical onset and rate of initial progression of disease severity. The relationship between CAG length and survival in Huntington disease is less studied. To address this, we obtained the complete Registry HD database from the European Huntington Disease Network and reanalyzed the time from reported age of disease onset until death. We conducted semiparametric proportional hazards modeling of 8,422 participants who had experienced onset of clinical Huntington disease, either retrospectively or prospectively. Of these, 826 had a recorded age of death. To avoid biased model estimates, retrospective onset ages were represented by left truncation at study entry. After controlling for onset age, which tends to be younger in those with longer CAG repeat lengths, we found that CAG length had a substantial and highly significant influence upon survival time after disease onset. For a fixed age of onset, longer CAG expansions were predictive of shorter survival. This is consistent with other known relationships between CAG length and disease severity. We also show that older onset age predicts shorter lifespan after controlling for CAG length and that the influence of CAG on survival length is substantially greater in women. We demonstrate that apparent contradictions between these and previous analyses of the same data are primarily due to the question of whether to control for clinical onset age in the analysis of time until death.

SUBMITTER: Langbehn DR

PROVIDER: S-EPMC8764269 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Factors associated with HD CAG repeat instability in Huntington disease.

Project description:The Huntington disease (HD) CAG repeat exhibits dramatic instability when transmitted to subsequent generations. The instability of the HD disease allele in male intergenerational transmissions is reflected in the variability of the CAG repeat in DNA from the sperm of male carriers of the HD gene.In this study, we used a collection of 112 sperm DNAs from male HD gene-positive members of a large Venezuelan cohort to investigate the factors associated with repeat instability. We confirm previous observations that CAG repeat length is the strongest predictor of repeat-length variability in sperm, but we did not find any correlation between CAG repeat instability and either age at the time of sperm donation or affectedness status. We also investigated transmission instability for 184 father-offspring and 311 mother-offspring pairs in this Venezuelan pedigree. Repeat-length changes were dependent upon the sex of the transmitting parent and parental CAG repeat length but not parental age or birth order. Unexpectedly, in maternal transmissions, repeat-length changes were also dependent upon the sex of the offspring, with a tendency for expansion in male offspring and contraction in female offspring.Significant sibling-sibling correlation for repeat instability suggests that genetic factors play a role in intergenerational CAG repeat instability.

| S-EPMC2705129 | biostudies-literature

CAG Repeat Not Polyglutamine Length Determines Timing of Huntington's Disease Onset.

Project description:Variable, glutamine-encoding, CAA interruptions indicate that a property of the uninterrupted HTT CAG repeat sequence, distinct from the length of huntingtin's polyglutamine segment, dictates the rate at which Huntington's disease (HD) develops. The timing of onset shows no significant association with HTT cis-eQTLs but is influenced, sometimes in a sex-specific manner, by polymorphic variation at multiple DNA maintenance genes, suggesting that the special onset-determining property of the uninterrupted CAG repeat is a propensity for length instability that leads to its somatic expansion. Additional naturally occurring genetic modifier loci, defined by GWAS, may influence HD pathogenesis through other mechanisms. These findings have profound implications for the pathogenesis of HD and other repeat diseases and question the fundamental premise that polyglutamine length determines the rate of pathogenesis in the "polyglutamine disorders."

| S-EPMC6700281 | biostudies-literature

CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion.

Project description:ObjectiveAge at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs.MethodsWe modeled natural log-transformed age at onset as a function of CAG repeat lengths of expanded and normal alleles and their interaction by linear regression.ResultsAn apparently significant effect of interaction on age at motor onset among 4,068 subjects was dependent on a single outlier data point. A rigorous statistical analysis with a well-behaved dataset that conformed to the fundamental assumptions of linear regression (e.g., constant variance and normally distributed error) revealed significance only for the expanded CAG repeat, with no effect of the normal CAG repeat. Ten subjects with 2 expanded alleles showed an age at motor onset consistent with the length of the larger expanded allele.ConclusionsNormal allele CAG length, interaction between expanded and normal alleles, and presence of a second expanded allele do not influence age at onset of motor manifestations, indicating that the rate of HD pathogenesis leading to motor diagnosis is determined by a completely dominant action of the longest expanded allele and as yet unidentified genetic or environmental factors.

| S-EPMC3306163 | biostudies-literature

Huntington CAG repeat size does not modify onset age in familial Parkinson's disease: the GenePD study.

Project description:The ATP/ADP ratio reflects mitochondrial function and has been reported to be influenced by the size of the Huntington disease gene (HD) repeat. Impaired mitochondrial function has long been implicated in the pathogenesis of Parkinson's disease (PD), and therefore, we evaluated the relationship of the HD CAG repeat size to PD onset age in a large sample of familial PD cases. PD affected siblings (n = 495), with known onset ages from 248 families, were genotyped for the HD CAG repeat. Genotyping failed in 11 cases leaving 484 for analysis, including 35 LRRK2 carriers. All cases had HD CAG repeats (range, 15-34) below the clinical range for HD, although 5.2% of the sample (n = 25) had repeats in the intermediate range (the intermediate range lower limit = 27; upper limit = 35 repeats), suggesting that the prevalence of intermediate allele carriers in the general population is significant. No relation between the HD CAG repeat size and the age at onset for PD was found in this sample of familial PD.

| S-EPMC2655323 | biostudies-literature

Length of Uninterrupted CAG, Independent of Polyglutamine Size, Results in Increased Somatic Instability, Hastening Onset of Huntington Disease.

Project description:Huntington disease (HD) is caused by a CAG repeat expansion in the huntingtin (HTT) gene. Although the length of this repeat is inversely correlated with age of onset (AOO), it does not fully explain the variability in AOO. We assessed the sequence downstream of the CAG repeat in HTT [reference: (CAG)n-CAA-CAG], since variants within this region have been previously described, but no study of AOO has been performed. These analyses identified a variant that results in complete loss of interrupting (LOI) adenine nucleotides in this region [(CAG)n-CAG-CAG]. Analysis of multiple HD pedigrees showed that this LOI variant is associated with dramatically earlier AOO (average of 25 years) despite the same polyglutamine length as in individuals with the interrupting penultimate CAA codon. This LOI allele is particularly frequent in persons with reduced penetrance alleles who manifest with HD and increases the likelihood of presenting clinically with HD with a CAG of 36-39 repeats. Further, we show that the LOI variant is associated with increased somatic repeat instability, highlighting this as a significant driver of this effect. These findings indicate that the number of uninterrupted CAG repeats, which is lengthened by the LOI, is the most significant contributor to AOO of HD and is more significant than polyglutamine length, which is not altered in these individuals. In addition, we identified another variant in this region, where the CAA-CAG sequence is duplicated, which was associated with later AOO. Identification of these cis-acting modifiers have potentially important implications for genetic counselling in HD-affected families.

| S-EPMC6556907 | biostudies-literature

Intergeneration CAG expansion in a Wuhan juvenile-onset Huntington disease family.

Project description:To make early diagnosis of IT15 gene mutation in a Wuhan juvenile-onset Huntington disease (HD) family, for providing them with genetic counseling, and making preparation for the further research on pathogenesis and experimental therapy of HD.According to the principle of informed consent, we extracted genomic DNA from peripheral blood samples and carried genetic diagnosis of pathogenic exon 1 of IT15 gene by modified touchdown PCR and DNA sequencing methods.Eight of twenty-five family members carried abnormal allele: III(10), III(12), III(14), IV(3), and V(2) carried (CAG) (48), IV(11) and IV(12) carried (CAG) (67), and IV(14) carried (CAG) (63), in contrast with the 8-25 CAG trinucleotides in the members of control group. IV(14) carried 15 more CAG trinucleotides than her father III(10).The results definitely confirm the diagnosis of HD and indicate the CAG trinucleotide repeat expansion of IT15 gene in this HD family. In addition, CAG expansion results in juvenile-onset and anticipation (characterized by earlier age of onset and increasing severity) of the patient IV(12).

| S-EPMC5550581 | biostudies-other

Linking SNPs to CAG repeat length in Huntington's disease patients.

Project description:Allele-specific silencing using small interfering RNAs targeting heterozygous single-nucleotide polymorphisms (SNPs) is a promising therapy for human trinucleotide repeat diseases such as Huntington's disease. Linking SNP identities to the two HTT alleles, normal and disease-causing, is a prerequisite for allele-specific RNA interference. Here we describe a method, SNP linkage by circularization (SLiC), to identify linkage between CAG repeat length and nucleotide identity of heterozygous SNPs using Huntington's disease patient peripheral blood samples.

| S-EPMC2587014 | biostudies-other

Characterization of the Huntington intermediate CAG repeat expansion phenotype in PHAROS.

Project description:ObjectivesWe aimed to describe the clinical phenotype conferred by the intermediate-length huntingtin allele CAG repeat expansion in a population-based study.MethodsThe Prospective Huntington At Risk Observational Study (PHAROS) enrolled adults at risk for Huntington disease (HD). They were assessed approximately every 9 months with the Unified Huntington's Disease Rating Scale (UHDRS) by investigators unaware of participants' gene status. UHDRS scores were compared according to the Huntingtin gene CAG repeat number: expanded >36, intermediate 27-35, and nonexpanded controls <26.ResultsFifty (5.1%) of the 983 participants had an intermediate allele (IA). They were similar to controls on UHDRS motor, cognitive, and functional measures, but significantly worse behaviorally on apathy and suicidal ideation. On 5 of the 9 other behavioral items and on total behavior, the IA group's scores were worse than those of controls and expanded participants, who themselves scored significantly worse than controls on 6 behavioral measures. Retention rates at 4 years were 48% for the IA group compared to 58% and 60% for the expanded and control groups.ConclusionsIn a cohort at risk for HD, the IA was associated with significant behavioral abnormalities but normal motor and cognition. This behavioral phenotype may represent a prodromal stage of HD, with the potential for subsequent clinical manifestations, or be part of a distinct phenotype conferred by pathology independent of the CAG expansion length.

| S-EPMC3716408 | biostudies-literature

Germ-line CAG repeat instability causes extreme CAG repeat expansion with infantile-onset spinocerebellar ataxia type 2.

Project description:The spinocerebellar ataxias (SCA) are a genetically and clinically heterogeneous group of diseases, characterized by dominant inheritance, progressive cerebellar ataxia and diverse extracerebellar symptoms. A subgroup of the ataxias is caused by unstable CAG-repeat expansions in their respective genes leading to pathogenic expansions of polyglutamine stretches in the encoded proteins. In general, unstable CAG repeats have an uninterrupted CAG repeat, whereas stable CAG repeats are either short or interrupted by CAA codons, which - like CAG codons - code for glutamine. Here we report on an infantile SCA2 patient who, due to germ-line CAG repeat instability in her father, inherited an extremely expanded CAG repeat in the SCA2 locus. Surprisingly, the expanded allele of the father was an interrupted CAG repeat sequence. Furthermore, analyses of single spermatozoa showed a high frequency of paternal germ-line repeat sequence instability of the expanded SCA2 locus.

| S-EPMC3658194 | biostudies-literature

Somatic expansion of the Huntington's disease CAG repeat in the brain is associated with an earlier age of disease onset.

Project description:The age of onset of Huntington's disease (HD) is determined primarily by the length of the HD CAG repeat mutation, but is also influenced by other modifying factors. Delineating these modifiers is a critical step towards developing validated therapeutic targets in HD patients. The HD CAG repeat is somatically unstable, undergoing progressive length increases over time, particularly in brain regions that are the targets of neurodegeneration. Here, we have explored the hypothesis that somatic instability of the HD CAG repeat is itself a modifier of disease. Using small-pool PCR, we quantified somatic instability in the cortex region of the brain from a cohort of HD individuals exhibiting phenotypic extremes of young and old disease onset as predicted by the length of their constitutive HD CAG repeat lengths. After accounting for constitutive repeat length, somatic instability was found to be a significant predictor of onset age, with larger repeat length gains associated with earlier disease onset. These data are consistent with the hypothesis that somatic HD CAG repeat length expansions in target tissues contribute to the HD pathogenic process, and support pursuing factors that modify somatic instability as viable therapeutic targets.

| S-EPMC2714728 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data