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Selective forces acting on spinocerebellar ataxia type 3/ Machado–Joseph disease recurrency: A systematic review and meta‐analysis
Author(s) -
Sena Lucas Schenatto,
Santos Pinheiro Jordânia,
SaraivaPereira Maria Luiza,
Jardim Laura Bannach
Publication year - 2021
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.13888
Subject(s) - spinocerebellar ataxia , machado–joseph disease , anticipation (artificial intelligence) , trinucleotide repeat expansion , allele , ataxia , genetics , disease , age of onset , meta analysis , biology , medicine , neuroscience , gene , artificial intelligence , computer science
Abstract Spinocerebellar ataxia type 3/Machado–Joseph disease (SCA3/MJD) is a dominant neurodegenerative disease caused by the expansion of a CAG repeat tract in ATXN3 . Anticipation and worsening of clinical picture in subsequent generations were repeatedly reported, but there is no indication that SCA3/MJD frequency is changing. Thus, we performed a systematic review and meta‐analysis on phenomena with potential effect on SCA3/MJD recurrency in populations: instability of CAG repeat transmissions, anticipation, fitness, and segregation of alleles. Transmission of the mutant allele was associated with an increase of 1.23 CAG repeats in the next generation, and the average change in age at onset showed an anticipation of 7.75 years per generation; but biased recruitments cannot be ruled out. Affected SCA3/MJD individuals had 45% more children than related controls. Transmissions from SCA3/MJD carriers showed that the expanded allele was segregated in 64% of their children. In contrast, transmissions from normal subjects showed that the minor allele was segregated in 54%. The present meta‐analysis concluded that there is a segregation distortion favoring the expanded allele, among children of carriers. Therefore, further studies on transmissions and anticipation phenomena as well as more observations about fertility are required to clarify these selective forces over SCA3/MJD.