Evaluating the causality of novel sequence variants in the prion protein gene by example

Abstract

The estimation of pathogenicity and penetrance of novel prion protein gene (PRNP) variants presents significant challenges, particularly in the absence of family history, which precludes the application of Mendelian segregation. Moreover, the ambiguities of prion disease pathophysiology renders conventional in silico predictions inconclusive. Here, we describe 2 patients with rapid cognitive decline progressing to akinetic mutism and death within 10 weeks of symptom onset, both of whom possessed the novel T201S variant in PRNP. Clinically, both satisfied diagnostic criteria for probable sporadic Creutzfeldt-Jakob disease and in one, the diagnosis was confirmed by neuropathology. While computational analyses predicted that T201S was possibly deleterious, molecular strain typing, prion protein structural considerations, and calculations leveraging large-scale population data (gnomAD) indicate that T201S is at best either of low penetrance or nonpathogenic. Thus, we illustrate the utility of harnessing multiple lines of prion disease–specific evidence in the evaluation of the T201S variant, which may be similarly applied to assess other novel variants in PRNP.

Case report of homozygous E200D mutation of PRNP in apparently sporadic Creutzfeldt-Jakob disease

“…Family history is a good guide to help decision making about the penetrance of novel PRNP variants, however in this case we would not expect a family history as the parents are expected to be heterozygous carriers of a benign variant. In our opinion, it seems likely that the homozygous E200D genotype was causal in this patient, the alternative possibility is of a coincidental occurrence of sCJD with a genotype of PRNP never before observed [ 4 ]. The situation seems similar to the Q212P variant of PRNP which appears to have low penetrance in the heterozygous state, but has caused an atypical early onset prion disease in the homozygous state [ 5 ].…”

<p>Novel prion mutation (p.Tyr225Cys) in a Korean patient with atypical Creutzfeldt–Jakob disease</p>

“…Structural predictions could be helpful in making hypotheses on the putative disturbing mechanisms of novel mutations; however, these models may not be consistent with in vivo disturbances. In silico modeling on Tyr225Cys could not fully demonstrate the damaging impact of mutation on prion protein 23…”

“…In GnomAD, one European individual possessed the p.Tyr225Cys variant. Thus far, no report was available on p.Tyr225Cys in regard to any disease phenotype, and it was defined as “singleton” or a very low-frequency variant 18,23. Penetrance of this variant was suggested to be small.…”

“…Rare variants found in few patients and/or unaffected individuals could be difficult to classify especially without family history. It would be complicated to estimate the pathogenicity of prion variants, neutral or possibly progressions into disease phenotype 18,23…”

Mutations in Prion Protein Gene: Pathogenic Mechanisms in C-Terminal vs. N-Terminal Domain, a Review

“…Taken together, we might consider the N- and C-terminal domains equally important from the standpoint of pathogenic mechanisms of causative mutations of PRNP found in inherited prion diseases. Novel mutations [84,85] (Table 1), with unclear pathogenicity (such as G127S, N171S, P238S, [31]) or associated with clinical phenotypes different from typical prion diseases [86], should be carefully studied, in particular, in view of these recently described pathogenic mechanisms. Further specific pathological, biochemical, and molecular studies are warranted [87] to investigate how variations in these domains might trigger the extreme phenotypic variability associated with the PrP protein, in terms of the pathogenicity towards neurodegeneration and not towards the specific typical prion diseases.…”