title: Spinocerebellar ataxia type 3/Machado-Joseph disease: segregation patterns and factors influencing instability of expanded CAG transmissions.
abstract: Controversies about Mendelian segregation and CAG expansion (CAGexp) instabilities during meiosis in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) need clarification. Additional evidence about these issues was obtained from the cohort of all SCA3/MJD individuals living in South Brazil. A survey was carried out to update information registered since 2001. Deaths were checked with the Public Information System, and data was made anonymous. Anticipation and delta-CAGexp from parent-offspring pairs, and delta-CAGexp between siblings were obtained. One hundred and fifty-nine families (94% of the entire registry) were retrieved, comprising 3725 living individuals as of 2015, 625 of these being symptomatic. Minimal prevalence was 6:100,000. Carriers of a CAGexp represented 65.6% of sibs in the genotyped offspring (p < 0.001). Median instability was larger among paternal than maternal transmissions, and instabilities correlated with anticipation (r = 0.38; p = 0.001). Age of the parent correlated to delta-CAGexp among 115 direct parent-offspring CAGexp transmissions (ρ = 0.23, p = 0.014). In 98 additional kindreds, the delta-CAGexp between 269 siblings correlated with their delta-of-age (ρ = 0.27, p < 0.0001). SCA3/MJD was associated with a segregation distortion favoring the expanded allele in our cohort. Instability of expansion during meiosis was weakly influenced by the age of the transmitting parent at the time of conception.
authors.affiliation: Programa de Pós-Graduação em Ciências Médicas, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: G N
authors.initials: GN
authors.lastname: Souza
authors.affiliation: Programa de Pós-Graduação em Ciências Médicas, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: N
authors.initials: N
authors.lastname: Kersting
authors.affiliation: Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: A C
authors.initials: AC
authors.lastname: Krum-Santos
authors.affiliation: Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: A S P
authors.initials: AS
authors.lastname: Santos
authors.affiliation: Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.|Laboratório de Identificação Genética, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
authors.forename: G V
authors.initials: GV
authors.lastname: Furtado
authors.affiliation: Faculdade de Serviço Social, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: D
authors.initials: D
authors.lastname: Pacheco
authors.affiliation: Escola de Enfermagem, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: T A
authors.initials: TA
authors.lastname: Gonçalves
authors.affiliation: Laboratório de Identificação Genética, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.|Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
authors.forename: J A
authors.initials: JA
authors.lastname: Saute
authors.affiliation: Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.|Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.|Departamento de Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.|Instituto de Genética Médica Populacional (INAGEMP), Porto Alegre, Brazil.
authors.forename: L
authors.initials: L
authors.lastname: Schuler-Faccini
authors.affiliation: Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.|Laboratório de Identificação Genética, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
authors.forename: E P
authors.initials: EP
authors.lastname: Mattos
authors.affiliation: Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.|Laboratório de Identificação Genética, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.|Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.|Instituto de Genética Médica Populacional (INAGEMP), Porto Alegre, Brazil.|Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: M L
authors.initials: ML
authors.lastname: Saraiva-Pereira
authors.affiliation: Programa de Pós-Graduação em Ciências Médicas, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.|Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.|Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.|Laboratório de Identificação Genética, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.|Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.|Instituto de Genética Médica Populacional (INAGEMP), Porto Alegre, Brazil.|Departamento de Medicina Interna, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: L B
authors.initials: LB
authors.lastname: Jardim
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D017668:Age of Onset; D000483:Alleles; D058070:Asymptomatic Diseases; D000067699:Ataxin-3 / Q000235:genetics*; D020090:Chromosome Segregation; D005260:Female; D005787:Gene Frequency; D042822:Genomic Instability; D006579:Heterozygote; D006801:Humans; D040582:Inheritance Patterns; D017827:Machado-Joseph Disease / Q000235:genetics* / Q000473:pathology; D008297:Male; D008540:Meiosis; D010375:Pedigree; D012097:Repressor Proteins / Q000235:genetics*; D012720:Severity of Illness Index; D012737:Sex Factors; D035781:Siblings; D019680:Trinucleotide Repeat Expansion
chemical_list: D012097:Repressor Proteins; C092341:ATXN3 protein, human; D000067699:Ataxin-3
keywords: CAG expansion instabilities; CAG expansion transmission; MJD; Machado-Joseph disease; SCA3; minimal prevalence; segregation distortion; spinocerebellar ataxia type 3