title: Overcoming artefact: anticipation in 284 Portuguese kindreds with familial amyloid polyneuropathy (FAP) ATTRV30M.
abstract: BACKGROUND
  Early-onset (≤40 years) and later-onset (≥50 years) cases of familial amyloid polyneuropathy (FAP) ATTRV30M are not different entities, often coexisting in the same family, and showing anticipation (earlier age-at-onset (AO) in younger generations, usually associated with more severe phenotype). Historically, anticipation has been ascribed to ascertainment biases. Our aim was to study anticipation in a very large number of FAP kindreds, removing possible biases, and gain further insight into parent-of-origin effects.
  
  
  METHODS
  We analysed 926 parent-offspring pairs (from the Unidade Clínica de Paramiloidose roster, collected in 70 years), both clinically observed and had well-established AO, correcting for intrafamilial correlations.
  
  
  RESULTS
  Women had a significantly higher AO, either for daughters (mean: 33.70, SD: 6.84) vs sons (29.43, 6.08); or mothers (39.57, 11.75) vs. fathers (35.62, 11.62). Also, 291 pairs showed marked anticipation (≥10 years); the transmitting parent was the mother in 203 pairs. Mother-son pairs showed larger anticipation (10.43, 9.34), while father-daughter pairs showed only a residual anticipation (1.23, 9.77). Gender of offspring and parents was highly significant (with no interaction). To remove possible biases, we repeated analyses: (1) excluding the proband; (2) removing pairs with simultaneous onset; and (3) excluding offspring born after 1960. Anticipation was found in all subsamples, with the same trend for a parent-of-origin effect. Noteworthy, parents with AO ≤40 years never had offspring with AO ≥50.
  
  
  CONCLUSIONS
  These findings confirm anticipation as a true biological phenomenon, also in FAP ATTRV30M. Acknowledgment of anticipation may have important clinical implications in genetic counselling of offspring and in follow-up of mutation carriers.
authors.affiliation: UnIGENe, IBMC-Instituto Biologia Molecular Celular, Universidade do Porto, , Porto, Portugal.
authors.forename: Carolina
authors.initials: C
authors.lastname: Lemos
authors.forename: Teresa
authors.initials: T
authors.lastname: Coelho
authors.forename: Miguel
authors.initials: M
authors.lastname: Alves-Ferreira
authors.forename: Ana
authors.initials: A
authors.lastname: Martins-da-Silva
authors.forename: Jorge
authors.initials: J
authors.lastname: Sequeiros
authors.forename: Denisa
authors.initials: D
authors.lastname: Mendonça
authors.forename: Alda
authors.initials: A
authors.lastname: Sousa
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D028227:Amyloid Neuropathies, Familial / Q000235:genetics*; D020132:Anticipation, Genetic / Q000235:genetics*; D015982:Bias; D005190:Family; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D011174:Portugal; D012737:Sex Factors; D035781:Siblings; D055815:Young Adult
keywords: AMYLOID; AUTONOMIC; EPIDEMIOLOGY; GENETICS; NEUROEPIDEMIOLOGY