The estimation of pathogenicity and penetrance of novel gene variants presents significant challenges, particularly with Mendelian segregation analysis in the absence of a family history. Here, we illustrate the value of an integrated approach with the utilisation of available large-scale population data. A 76-year old woman with no family history of Creutzfeldt-Jakob Disease (CJD) presented with abrupt onset upper limb tremor, evolving rapidly into gait apraxia, non-fluent dysphasia, abulia, visual hallucinations, myoclonus, akinetic mutism and death over 8 weeks. Her Magnetic Resonance Imaging (MRI) demonstrated cortical and basal ganglia diffusion restriction while the EEG showed generalised periodic complexes. Prion protein gene PRNP sequencing unexpectedly revealed a T201S mutation; codon 129 was methionine homozygous (MM). In silico missense substitution analysis methods predicted non-radical changes given the structural similarities of both serine and threonine with polar uncharged side chains. Despite that, T201S is only detected in 1 in 60,706 individuals within the Broad Institute's ExAC large-scale population genomic database. Literature search identified 1 other pathologically confirmed case of CJD with T201S mutation and 129MM, also without family history in Danish surveillance data. Overall, this would suggest that the variant is likely to be deleterious, but probably of incomplete penetrance.
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