title: Parental age effects, but no evidence for an intrauterine effect in the transmission of myotonic dystrophy type 1.
abstract: Myotonic dystrophy type 1 (DM1) is caused by the expansion of an unstable CTG repeat (g.17294_17296(45_1000)) with more repeats associated with increased disease severity and reduced age at onset. Expanded disease-associated alleles are highly unstable in both the germline and soma. Germline instability is expansion biased, providing a molecular explanation for anticipation. Somatic instability is expansion biased, size- and age-dependent, features that have compromised genotype-phenotype correlations and intergenerational studies. We corrected these confounding factors by estimating the progenitor allele length in 54 father-offspring and 52 mother-offspring pairs in Costa Rican DM1 families. Not surprisingly, we found major parental allele length effects on the size of the allele transmitted, the magnitude of the intergenerational length change, the age at onset in the next generation and the degree of anticipation in both male and female transmissions. We also detected, for the first time, an age-of-parent effect for both male and female transmission. Interestingly, we found no evidence for an intrauterine effect in the transmission of congenital DM1, suggesting previous reports may have been an artefact of age-dependent somatic instability and sampling bias. These data provide new insights into the germline dynamics of the CTG repeat and opportunities for providing additional advice and more accurate risk assessments to prospective parents in DM1 families.
authors: 1] Cuidad Universitaria Rodrigo Facio, Instituto de Investigaciones en Salud (INISA), Universidad de Costa Rica, San José, Costa Rica [2] Escuela de Medicina, Universidad de Costa Rica, San José, Costa Rica [3] Centro de Investigaciones en Neurociencias, Universidad de Costa Rica, San José, Costa Rica.
authors: Fernando
authors: F
authors: Morales
authors: 1] Cuidad Universitaria Rodrigo Facio, Instituto de Investigaciones en Salud (INISA), Universidad de Costa Rica, San José, Costa Rica [2] Centro de Investigaciones en Neurociencias, Universidad de Costa Rica, San José, Costa Rica.
authors: Melissa
authors: M
authors: Vásquez
authors: 1] Cuidad Universitaria Rodrigo Facio, Instituto de Investigaciones en Salud (INISA), Universidad de Costa Rica, San José, Costa Rica [2] Escuela de Medicina, Universidad de Costa Rica, San José, Costa Rica [3] Centro de Investigaciones en Neurociencias, Universidad de Costa Rica, San José, Costa Rica.
authors: Patricia
authors: P
authors: Cuenca
authors: Instituto de Investigaciones Psicológicas (IIP), Universidad de Costa Rica, San José, Costa Rica.
authors: Domingo
authors: D
authors: Campos
authors: 1] Cuidad Universitaria Rodrigo Facio, Instituto de Investigaciones en Salud (INISA), Universidad de Costa Rica, San José, Costa Rica [2] Escuela de Nutrición, Universidad de Costa Rica, San José, Costa Rica.
authors: Carolina
authors: C
authors: Santamaría
authors: Laboratorio de Neurofisiología (Neurolab), Curridabat, San José, Costa Rica.
authors: Gerardo
authors: G
authors: Del Valle
authors: Servicio de Neurología, Hospital Nacional de Niños, San José, Costa Rica.
authors: Roberto
authors: R
authors: Brian
authors: Servicio de Neurología, Hospital San Juan de Dios, San José, Costa Rica.
authors: Mauricio
authors: M
authors: Sittenfeld
authors: Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
authors: Darren G
authors: DG
authors: Monckton
mesh_terms: D000328:Adult; D000367:Age Factors; D017668:Age of Onset; D000483:Alleles; D020132:Anticipation, Genetic; D003364:Costa Rica; D005190:Family; D005260:Female; D006801:Humans; D040582:Inheritance Patterns; D008297:Male; D009223:Myotonic Dystrophy / Q000453:epidemiology* / Q000209:etiology*; D010290:Parents; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012737:Sex Factors; D019680:Trinucleotide Repeat Expansion