Highly reduced penetrance in a family with a THAP1 nonsense mutation: Role of THAP1 expression?

A large number of pathogenic mutation carriers eventually do not develop the disease in question, a phenomenon known as ‘reduced penetrance’. Understanding the mechanisms underlying reduced penetrance has a particularly high imperative given that it may be viewed as a means of ‘endogenous’ disease protection [1]. For many genetic dystonias such as DYT-THAP1 (DYT6 dystonia) the penetrance is highly reduced (to ∼50%). DYT-THAP1 is caused by heterozygous loss-of-function mutations in THAP1. It usually manifests in childhood or adolescence (75% of affected carriers with age at onset <30 years) and starts with brachial or cervical dystonia.