Τίτλος:
Wide range of reduced penetrance alleles in spinal and bulbar muscular
atrophy: a model-based approach
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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) approximate to 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.
Συγγραφείς:
Laskaratos, Achilleas
Breza, Marianthi
Karadima, Georgia and
Koutsis, Georgios
Περιοδικό:
JOURNAL OF MEDICAL GENETICS
Εκδότης:
BMJ Publishing Group
Λέξεις-κλειδιά:
clinical genetics; neurology
DOI:
10.1136/jmedgenet-2020-106963
