title: Germline mutational dynamics in myotonic dystrophy type 1 males: allele length and age effects.
abstract: BACKGROUND
  The CTG repeat expansion causing myotonic dystrophy type 1 is unstable in the germline, and frequent intergenerational length changes are observed, giving rise to the unusual genetics of the disorder. The repeat is also somatically unstable, and expanded alleles accumulate throughout life, thus compromising simple measures of intergenerational stability.
  
  
  OBJECTIVE
  To gain a better understanding of the intergenerational dynamics of the DM1 repeat in the male germline.
  
  
  METHODS
  We used sensitive small pool PCR procedures to analyze sperm and somatic DNA from 22 DM1 men of different ages, CTG repeat length, and clinical form.
  
  
  RESULTS
  High levels of repeat length variation heavily biased toward further expansions were observed in the sperm of all DM1 men. Progenitor allele length was revealed as a major modifier of interindividual variation, with the largest length changes observed for premutation and protomutation alleles and the highest frequency of contractions in full mutation alleles. However, despite clear increases in the degree of somatic mosaicism, no differences were observed in replicate sperm samples obtained from two men during a 4-year period.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Servei de Genètica, Hospital de Sant Pau, Barcelona, Spain. mmartorells@hsp.santpau.es
authors.forename: L
authors.initials: L
authors.lastname: Martorell
authors.forename: J
authors.initials: J
authors.lastname: Gámez
authors.forename: M L
authors.initials: ML
authors.lastname: Cayuela
authors.forename: F K
authors.initials: FK
authors.lastname: Gould
authors.forename: J P
authors.initials: JP
authors.lastname: McAbney
authors.forename: T
authors.initials: T
authors.lastname: Ashizawa
authors.forename: D G
authors.initials: DG
authors.lastname: Monckton
authors.forename: M
authors.initials: M
authors.lastname: Baiget
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics; D018095:Germ-Line Mutation; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009223:Myotonic Dystrophy / Q000235:genetics*; D016133:Polymerase Chain Reaction; D013094:Spermatozoa / Q000737:chemistry; D018911:Trinucleotide Repeats
chemical_list: D004247:DNA