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Research paper
Overcoming artefact: anticipation in 284 Portuguese kindreds with familial amyloid polyneuropathy (FAP) ATTRV30M
  1. Carolina Lemos1,2,
  2. Teresa Coelho3,
  3. Miguel Alves-Ferreira1,
  4. Ana Martins-da-Silva3,
  5. Jorge Sequeiros1,2,
  6. Denisa Mendonça2,4,
  7. Alda Sousa1,2
  1. 1UnIGENe, IBMC—Instituto Biologia Molecular Celular, Universidade do Porto, Porto, Portugal
  2. 2ICBAS, Instituto Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
  3. 3Unidade Clínica de Paramiloidose (UCP), Centro Hospitalar do Porto (CHP), Porto, Portugal
  4. 4ISPUP, Instituto de Saúde Pública, Universidade do Porto, Porto, Portugal
  1. Correspondence to Dr Carolina Lemos, Invited Auxiliary Professor, ICBAS, UnIGENe, IBMC, University of Porto, Porto 4150-180, Portugal; clclemos{at}


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.


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