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Original research
Wide range of reduced penetrance alleles in spinal and bulbar muscular atrophy: a model-based approach
  1. Achilleas Laskaratos,
  2. Marianthi Breza,
  3. Georgia Karadima,
  4. Georgios Koutsis
  1. Neurogenetics Unit, 1st Department of Neurology, National and Kapodistrian University of Athens, Eginition University Hospital, Athens, Greece
  1. Correspondence to Dr Georgios Koutsis, Neurogenetics Unit, 1st Department of Neurology, National and Kapodistrian University of Athens, Eginition University Hospital, Athens 11528, Greece; gkoutsi2{at}; gkoutsis{at}


Background Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy’s disease, is an X-linked motor neuron disorder caused by an expanded CAG repeat in the gene coding for the androgen receptor (AR). The range and significance of reduced penetrance alleles in SBMA has not been fully determined to date. We presently sought to determine the range of reduced penetrance alleles in SBMA.

Methods Through systematic literature review and meta-analysis, we collected and analysed data from 2576 patients with SBMA and compared the distributions of the CAG repeat number (CAG)n in the AR gene between patients and 112 248 control alleles of the general population.

Results Our analysis revealed an unexpectedly high frequency of expanded SBMA-associated alleles, with (CAG)n ≥35 present in 107/100,000 and (CAG)n ≥38 present in 27/100,000 of the general population. Consequently, we suggest an updated model describing the distribution of expanded alleles in the general population. We argue against the established cut-off principle for the penetrance of SBMA and suggest that penetrance gradually increases from 35 to approximately 46 (CAG)n, above which it reaches a plateau approaching maximum value.

Conclusion Asymptomatic men of the general population with no/unknown SBMA family history are free of risk when carrying (CAG)n ≤34, are at intermediate but increasing risk for developing SBMA when carrying (CAG)n ≈35–46 and have close to 100% risk of developing the disease when carrying (CAG)n ≥47. The above observations should be helpful and clinically useful when providing genetic counselling to individuals and families bearing SBMA-associated alleles.

  • clinical genetics
  • neurology

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  • Contributors AL conceived the study, collected and analysed the data and prepared the manuscript. MB, GKa and GKo reviewed and edited the manuscript. GKo supervised the study. All authors agreed on the final version of the paper.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Map disclaimer The depiction of boundaries on this map does not imply the expression of any opinion whatsoever on the part of BMJ (or any member of its group) concerning the legal status of any country, territory, jurisdiction or area or of its authorities. This map is provided without any warranty of any kind, either express or implied.

  • Competing interests GKa has received research grants from Pfizer and provided consultation services for Roche. GKo has received research grants from Teva and Genesis Pharma and provided consultation services for and/or received honoraria from Novartis, Sanofi-Genzyme, Genesis Pharma, Specifar, Pfizer, Roche, Teva, Merck and Integris Pharma.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.

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