Age-dependent somatic expansion of the ATXN3 CAG repeat in the blood and buccal swab DNA of individuals with spinocerebellar ataxia type 3/Machado-Joseph disease.
Ahmed M Sidky, Ana Rosa Vieira Melo, Teresa T Kay, Mafalda Raposo, Manuela Lima, Darren G Monckton
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引用次数: 0
Abstract
Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is caused by the expansion of a genetically unstable polyglutamine-encoding CAG repeat in ATXN3. Longer alleles are generally associated with earlier onset and frequent intergenerational expansions mediate the anticipation observed in this disorder. Somatic expansion of the repeat has also been implicated in disease onset and slowing the rate of somatic expansion has been proposed as a therapeutic strategy. Here, we utilised high-throughput ultra-deep MiSeq amplicon sequencing to precisely define the number and sequence of the ATXN3 repeat, the genotype of an adjacent single nucleotide variant and quantify somatic expansion in blood and buccal swab DNA of a cohort of individuals with SCA3 from the Azores islands (Portugal). We revealed systematic mis-sizing of the ATXN3 repeat and high levels of inaccuracy of the traditional fragment length analysis that have important implications for attempts to identify modifiers of clinical and molecular phenotypes. Quantification of somatic expansion in blood DNA and multivariate regression revealed the expected effects of age at sampling and CAG repeat length, although the effect of repeat length was surprisingly modest with much stronger associations with age. We also observed an association of the downstream rs12895357 single nucleotide variant with the rate of somatic expansion, and a higher level of somatic expansion in buccal swab DNA compared to blood. These data suggest that the ATXN3 locus in SCA3 patients in blood or buccal swab DNA might serve as a good biomarker for clinical trials testing suppressors of somatic expansion with peripheral exposure.
期刊介绍:
Human Genetics is a monthly journal publishing original and timely articles on all aspects of human genetics. The Journal particularly welcomes articles in the areas of Behavioral genetics, Bioinformatics, Cancer genetics and genomics, Cytogenetics, Developmental genetics, Disease association studies, Dysmorphology, ELSI (ethical, legal and social issues), Evolutionary genetics, Gene expression, Gene structure and organization, Genetics of complex diseases and epistatic interactions, Genetic epidemiology, Genome biology, Genome structure and organization, Genotype-phenotype relationships, Human Genomics, Immunogenetics and genomics, Linkage analysis and genetic mapping, Methods in Statistical Genetics, Molecular diagnostics, Mutation detection and analysis, Neurogenetics, Physical mapping and Population Genetics. Articles reporting animal models relevant to human biology or disease are also welcome. Preference will be given to those articles which address clinically relevant questions or which provide new insights into human biology.
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