Germline mutational dynamics in myotonic dystrophy type 1 males

Abstract

Progenitor allele length is a major modifier of the mutational dynamics of the DM1 repeat in the male germline, but surprisingly age is not. Therefore, other as yet unidentified modifiers must be responsible for the considerable residual interindividual variation that cannot be accounted for by these factors.

Parental age effects, but no evidence for an intrauterine effect in the transmission of myotonic dystrophy type 1

“…This effect was much more pronounced for females, and was only apparent for males carrying pre-and proto-mutations (o80 repeats). These observations are consistent with the intraclass correlation between siblings, which was significant for female transmissions, but was not detectable for paternal transmissions; consistent with the very high levels of intra-individual variation observed by direct sperm analysis 25,30,33 and suggesting that inter-egg variation is less pronounced. Our analyses have also confirmed that the main driver of the size of the intergenerational length change is also parental ePAL.…”

“…10,13,[15][16][17][18][19] Full mutations (479 repeats) in males are highly unstable, but appear to be more likely to contract; consistent with direct sperm analyses. 25,30,33 In females, pre-and protomutations are relatively stable, but full mutations are much more unstable and biased towards much larger expansion than in males, consistent with the excess of transmitting mothers of CDM. 10,13,20,21 However, transmissions from mothers with very long alleles (4249 repeats) are less well explained by maternal ePAL and, as in males, appear to be more likely to contract.…”

“…However, there are no reports of a parental age effect in pedigree analyses, and even direct sperm DNA analyses have proven inconclusive. 33 In female transmission, a modest marginally significant increase in the size of intergenerational expansions with age was observed (r 2 ¼ 0.050, P ¼ 0.060, n ¼ 52; Figure 3a). In addition to the inherent variability in transmissions from a given individual, a possible confounding factor in detecting age effects are possible allele length-mediated sampling biases.…”

“…33 However, this was largely driven by a strong effect for males carrying proto-mutations o80 repeats (g.17294_17296 (50_79)). 33 Similarly, when male transmissions were split according to paternal ePAL, a significant correlation with the child's ePAL was observed for fathers carrying pre-and proto-mutations (38-79 repeats (g.17294_17296(38_79)); r 2 ¼ 0.109, P ¼ 0.017, n ¼ 43), but no length effect towards the transmission of larger alleles was observed for fathers with full mutations (480 repeats (g.17294_17296(80_3000)); r 2 ¼ 0.096, P ¼ 0.185, n ¼ 11; Figure 1). The ePAL in the mother was correlated with the ePAL in the child (r 2 ¼ 0.249, Po0.001, n ¼ 52; Figure 1).…”

“…The age effect revealed here for paternal transmissions from males with alleles o70 repeats is consistent with the effect observed in direct sperm DNA analyses in males with pre-and proto-mutations. 33 The allele length-dependent age effect on fecundity limits our ability to detect any possible age effect in males carrying larger expansions. Previous direct sperm analyses in such males did not reveal any evidence for changes in repeat length over time periods in which clear differences in somatic mosaicism were detectable.…”