Complex patterns of male germline instability and somatic mosaicism in myotonic dystrophy type 1

Abstract

The genetic basis of myotonic dystrophy type 1 (DM1) is the expansion of a CTG repeat in the 3' untranslated region of DM1PK. Once into the disease range, the repeat becomes highly unstable and is biased toward expansion in both somatic and germline tissues. Intergenerational differences usually reveal an increase in allele length, concordant with the clinical anticipation characteristic of DM1, but there have also been cases with intergenerational contractions of the repeat length, accompanied by apparent anticipation. In order to gain a better understanding of this intergenerational behaviour, we have obtained semen samples from six DM males and used single molecule analyses to compare the allele distributions present in their sperm and blood with those of their offspring. We have confirmed that the male germline mutational pathway is distinct from that of the soma, but the extent of variation is highly variable from one individual to another and not obviously correlated with progenitor allele length. Nonetheless, in all cases the alleles present in the father's sperm overlap with those observed in their offspring. These data also provide further indications that the interpretation of intergenerational transmissions by standard analyses is frequently compromised by the masking of germline differences by age-dependent somatic expansion in the parent.

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.…”

“…Combined SP-PCR analysis of sperm DNA in a small number of affected males with estimation of PAL in themselves and their offspring has suggested that some intergenerational transmissions have been mis-interpreted using the traditional approach. 25,30 We hypothesise that failure to take into account age-dependent somatic mosaicism has compromised the interpretation of previous pedigree analyses in DM1. To test this hypothesis, we recruited a large cohort of Costa Rican DM1 families and investigated intergenerational dynamics by estimating PAL in parents and offspring.…”

The reproductive outcome of female patients with myotonic dystrophy type 1 (DM1) undergoing PGD is not affected by the size of the expanded CTG repeat tract

“…Based on elevated FSH levels, with normal LH and serum testosterone levels, it is speculated that pituitary function could be abnormal in terms of a deficient feed back inhibition of FSH secretion by testosterone and inhibin B. On the other hand, and although the number of Sertoli cells is decreased as a result of Six5 gene mutation, spermatogenesis is rather thought to be impaired by functional abnormalities in Sertoli cell-germ cell and Sertoli cell-Leydig cell interactions, resulting in increased germ cell apoptosis [30]. At present there is insufficient evidence suggesting any effect of deficient Six5 expression on female gametogenesis.…”

Re-entry Circuit in Ventricular Tachycardia Due to Focal Fatty-fibrosis in a Patient with Myotonic Dystrophy

“…All reports concerning the correlation between CTG- repeat and disease severity were based on the analysis of CTG repeats expansion in each patient's leukocyte rather than in cardiomyocytes. We should focus on CTG repeats in cardiomyocytes when we make an attempt to investigate about the correlation between cardiac involvement and the CTG repeats expansion, as it was recently reported that somatic instability is often seen in patients of DM1 (22,23).…”