The Invitae Hereditary Prion Disease Test analyzes the PRNP gene, which is associated with a clinically heterogeneous spectrum of progressive neurodegenerative conditions characterized by dementia, ataxia, pyramidal and extrapyramidal features, sleep and sensory disturbances, and psychiatric manifestations. PRNP-related prion diseases include the genetic form of Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome, and fatal familial insomnia.
Individuals with clinical signs and symptoms of prion disease may benefit from diagnostic genetic testing to confirm the diagnosis, provide anticipatory guidance, and help determine which relatives are at risk.
In many cases, prion diseases have nonspecific or overlapping features with different types of dementia. In these cases, clinicians may want to consider the Invitae Combined Dementia and Amyotrophic Lateral Sclerosis Panel, which includes genes associated with various forms of dementia (including early-onset Alzheimer’s disease and frontotemporal dementia), and ALS. Clinicians may also consider the Invitae Hereditary Parkinson’s Disease and Parkinsonism Panel, as there is some clinical overlap between prion disease and parkinsonism.
Inherited prion diseases represent a spectrum of progressive neurodegenerative conditions associated with misfolding and aggregation of the prion protein within the brain. Historically labeled as distinct conditions such as genetic Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome, and fatal familial insomnia, they are now considered to represent a continuum of overlapping phenotypes that fall under the umbrella of prion diseases. The three major subtypes of hereditary prion disease may be categorized based on genotype, and can have variable clinical manifestations and age of onset, which ranges from early to late adulthood. The majority of affected individuals present with cognitive difficulties, ataxia, and dementia. The pathological hallmark of prion disease consists of the presence of spongiform changes and abnormal prion protein in the central nervous system (CNS) of affected individuals.
Genetic Creutzfeldt-Jakob disease (gCJD) is typically characterized by rapidly progressive dementia, cerebellar dysfunction (muscle incoordination with gait, visual, and speech abnormalities), and myoclonus. Over the course of the disorder, other features may develop, including tremors, spasticity and rigidity, behavioral changes, confusion, and depression. Certain genotypes are associated with a frontotemporal dementia-like phenotype, with initial features of personality change and aggressive behavior followed by more typical symptoms of CJD.
Gerstmann-Straussler-Scheinker syndrome (GSS) is typically a more slowly progressive disorder compared to gCJD, and is characterized by dementia, cerebellar ataxia, gait abnormalities, parkinsonian features, and abnormal reflexes in the lower extremities. Coordination problems are usually the presenting feature in individuals with GSS.
Fatal familial insomnia (FFI) is characterized by a rapidly progressive disease course. The primary feature is insomnia with marked reduction in sleep time and abnormal transition between different stages of sleep. Affected individuals may also experience features of ataxia, myoclonus, pyramidal signs, dysautonomia, and dysarthria.
Pathogenic variants in the PRNP gene are the only known cause of genetic prion diseases, and it is estimated that 100% of individuals with genetic forms of prion disease have a germline pathogenic variant in the PRNP gene.
Codon 129 status (p.Met129Met or p.Met129Val) within the PRNP gene has been reported to modify the clinical presentation of PRNP-related (and other) neurodegenerative disorders. When present in combination with the Pathogenic p.Asp178Asn variant, homozygosity for methionine at codon 129 has been reported to lead to the fatal familial insomnia (FFI) phenotype (PMID: 3762620). However, subsequent studies have not supported this finding (PMID: 16227536). This variant has also been reported to impact the age of onset of Alzheimer’s disease and sporadic Creutzfeldt-Jakob disease (PMID: 12601712, 16227536, 10443888). It has also been reported that homozygosity for methionine at codon 129 is associated with an earlier onset of FFI along with a shorter disease course, but this finding did not reach statistical significance (PMID: 24249784). In summary, no studies have conclusively proven that these polymorphisms have any modifying effect, and codon 129 status is thus not included in primary reports.
Hereditary prion diseases associated with mutations in the PRNP gene are inherited in an autosomal dominant manner.
Most pathogenic variants in the PRNP gene are associated with complete penetrance, with evidence for intrafamilial, age-dependent phenotypic variability. However, there is evidence for reduced penetrance in certain variants.
Overall, human prion diseases are rare, with a yearly incidence of 1 to 1.5 affected individuals per 1,000,000 individuals in the general population, and can be sporadic, genetic, or acquired. An estimated 85% of human prion disease is sporadic, due to the spontaneous conversion of normal prion protein to an abnormal, misfolded form. There are sporadic (non-genetic) forms of CJD and FFI. Acquired forms of prion disease (kuru, iatrogenic CJD, and variant CJD) account for less than 5% of human prion disease cases, and are caused by infection with abnormal prion protein from an external source. Genetic forms of prion disease caused by pathogenic variants in the PRNP gene account for an estimated 10-15% of all cases.
Genetic testing for hereditary prion diseases may confirm a suspected diagnosis or help to rule out the genetic forms of prion disease. A genetic diagnosis may also help inform recurrence risk, provide anticipatory guidance regarding disease progression (as genotype-phenotype correlations are well-characterized for the PRNP gene), and/or promote enrollment in clinical trials.
A genetic cause for prion disease may be suspected in individuals who have:
In addition to meeting one of the above criteria, individuals considering genetic testing for hereditary forms of prion disease should first receive thorough pre-test genetic counseling from a professional qualified to provide such counseling regarding the implications of testing for neurodegenerative disorders that have no known treatment or cure at this time.
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|
PRNP analysis does not include the octapeptide repeat region. PRNP codon 129 status is not included in reports (see Clinical Sensitivity section of prion disease test page for more information).