Factors Associated with Intergenerational Instability of ATXN3 CAG Repeat and Genetic Anticipation in Chinese Patients with Spinocerebellar Ataxia Type 3

Abstract

Spinocerebellar ataxia type 3 (SCA3) is caused by unstable expanded CAG repeats (expCAGs) in ATXN3. Factors associated with intergenerational instability (delta-expCAG) and genetic anticipation in SCA3 have never been reported in Chinese mainland. Here, we demonstrated that unstable transmissions occurred more often in sons than in daughters (91% vs 72%, Fisher's exact test, p = 0.012). The extended delta-expCAG of father-son transmissions was greater than that of mother-son transmissions (3.8 ± 2.3 repeats vs 1.6 ± 1.0 repeats, Mann-Whitney U, p = 0.001). Genetic anticipation was frequently observed between generations but not affected by the delta-expCAG.

Homozygous spinocerebellar ataxia type 3 in China: a case report

“…CAG repeat expansions are highly unstable in transmission from parents to offspring, and the transmission conditions of expansion, contraction, and stability account for 58.9%, 23.2%, and 17.8%, respectively, of Chinese SCA3. 13 The pattern of contraction and stable CAG repeats during transmission is found in the present homozygous patient, with the maternal transmission resulting in a contraction of -3 CAG repeats, and the paternal one resulting in a uniform transmission. Notably, this phenomenon differs from a previously reported case in which paternal transmission was more unstable than maternal transmission.…”

CAG repeat mosaicism is gene specific in spinocerebellar ataxias

“… 22 , 23 , 24 Anticipation explained by instability of the repeat size was described in all SCAs, with greater increase associated with paternal transmission in SCA1, 2, and 7. 22 , 23 , 25 , 26 , 27 , 28 …”

Polyglutamine Ataxias: Our Current Molecular Understanding and What the Future Holds for Antisense Therapies

“…Due to the nature of this type of mutation, there appears to be a common theme-the larger the expansion is, the earlier is the age of onset, and the more severe is the disease phenotype [8]. Additionally, these diseases typically follow what is known as 'genetic anticipation', whereby the expansion can increase in size with each successive generation [8,9]. Although caused by the same expansion mutation, the diseases present as clinically heterogenous, with some common features such as ataxia, speech and swallowing difficulties, as well as impaired hand, gait, and motor functions [10].…”