TY - JOUR
T1 - Longitudinal increases in somatic mosaicism of the expanded CTG repeat in myotonic dystrophy type 1 are associated with variation in age-at-onset
AU - Morales, Fernando
AU - Vásquez, Melissa
AU - Corrales, Eyleen
AU - Vindas-Smith, Rebeca
AU - Santamaría-Ulloa, Carolina
AU - Zhang, Baili
AU - Sirito, Mario
AU - Estecio, Marcos R.
AU - Krahe, Ralf
AU - Monckton, Darren G.
N1 - Funding Information:
This work was supported by the Muscular Dystrophy Association (www.mda.org, MDA200568 to F.M.); the Ministerio de Ciencia y Tecnolog?a de Costa Rica (www.micit.go.cr); the Consejo Nacional para Investigaciones Cient?ficas y Tecnol?gicas in Costa Rica (CONICIT) (www.conicit.go.cr) and the Universidad de Costa Rica (www.ucr.ac.cr).
Publisher Copyright:
© The Author(s) 2020. Published by Oxford University Press. All rights reserved
PY - 2020/8/1
Y1 - 2020/8/1
N2 - In myotonic dystrophy type 1 (DM1), somatic mosaicism of the (CTG)n repeat expansion is age-dependent, tissue-specific and expansion-biased. These features contribute toward variation in disease severity and confound genotype-to-phenotype analyses. To investigate how the (CTG)n repeat expansion changes over time, we collected three longitudinal blood DNA samples separated by 8-15 years and used small pool and single-molecule PCR in 43 DM1 patients. We used the lower boundary of the allele length distribution as the best estimate for the inherited progenitor allele length (ePAL), which is itself the best predictor of disease severity. Although in most patients the lower boundary of the allele length distribution was conserved over time, in many this estimate also increased with age, suggesting samples for research studies and clinical trials should be obtained as early as possible. As expected, the modal allele length increased over time, driven primarily by ePAL, age-at-sampling and the time interval. As expected, small expansions <100 repeats did not expand as rapidly as larger alleles. However, the rate of expansion of very large alleles was not obviously proportionally higher. This may, at least in part, be a result of the allele length-dependent increase in large contractions that we also observed. We also determined that individual-specific variation in the increase of modal allele length over time not accounted for by ePAL, age-at-sampling and time was inversely associated with individual-specific variation in age-at-onset not accounted for by ePAL, further highlighting somatic expansion as a therapeutic target in DM1.
AB - In myotonic dystrophy type 1 (DM1), somatic mosaicism of the (CTG)n repeat expansion is age-dependent, tissue-specific and expansion-biased. These features contribute toward variation in disease severity and confound genotype-to-phenotype analyses. To investigate how the (CTG)n repeat expansion changes over time, we collected three longitudinal blood DNA samples separated by 8-15 years and used small pool and single-molecule PCR in 43 DM1 patients. We used the lower boundary of the allele length distribution as the best estimate for the inherited progenitor allele length (ePAL), which is itself the best predictor of disease severity. Although in most patients the lower boundary of the allele length distribution was conserved over time, in many this estimate also increased with age, suggesting samples for research studies and clinical trials should be obtained as early as possible. As expected, the modal allele length increased over time, driven primarily by ePAL, age-at-sampling and the time interval. As expected, small expansions <100 repeats did not expand as rapidly as larger alleles. However, the rate of expansion of very large alleles was not obviously proportionally higher. This may, at least in part, be a result of the allele length-dependent increase in large contractions that we also observed. We also determined that individual-specific variation in the increase of modal allele length over time not accounted for by ePAL, age-at-sampling and time was inversely associated with individual-specific variation in age-at-onset not accounted for by ePAL, further highlighting somatic expansion as a therapeutic target in DM1.
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U2 - 10.1093/hmg/ddaa123
DO - 10.1093/hmg/ddaa123
M3 - Article
C2 - 32601694
AN - SCOPUS:85090253147
SN - 0964-6906
VL - 29
SP - 2496
EP - 2507
JO - Human molecular genetics
JF - Human molecular genetics
IS - 15
ER -