Tools for communicating risk for Parkinson’s disease

With genetic data provided from testing, risk estimates considered prior to testing can be revised and recalculated. With the addition of genetic testing, risk counseling becomes more precise and nuanced (Table 2). A corollary is that genetic test results can be personalized and refined with gathered histories on the patient. When estimating genetic risks using test results, it can be helpful to place them within the context of an individual’s age (risk increases over time for PD), ancestry (e.g., European vs Asian, Ashkenazi Jewish), and family history (both maternal and paternal)7.

Residual PD risk due to negative genetic test results

In both sporadic and familial forms of PD, in most populations, genetic results for major variants are usually negative11. Risk communication is still important for negative results since misperceptions may occur15. One commonly held misperception of patients is that a negative result on genetic testing means that there is not a genetic contribution or, even, that they do not have PD. Patients may infer that their children will not be at risk to develop disease. This will require clarification, with the reminder that typically PD is caused by multiple factors, including minor or unknown genetic ones not currently tested. An estimation of residual risk to relatives and asymptomatic patients following negative genetic testing can be provided based on available clinical and family histories and the scope of testing performed (refer to Table 2/Case 1 in Supplement). A reminder to the patient regarding how a PD diagnosis is made can also be helpful.

Negative genetic test results when the testing is narrow in scope or lacking can falsely reassure families. Another important caveat to communicate is that genetic data for PD have been collected mostly on European populations16. The result is that PD genetic test results and lab interpretations that appear “normal” may not be as informative for those from non-European populations.

Monogenic gene variants and PD risk

PD genetic test results, when positive, will commonly involve the major genes LRRK2, GBA1, and PRKN11. For these three genes and the other established PD genes, principles of monogenic inheritance will apply (Table 3) with some exceptions such as reduced penetrance and variable expressivity. Being familiar with these concepts (Table 4) and the various types of inheritance and associated risks—autosomal dominant, autosomal recessive, multifactorial and, less so, X-linked—will be important for risk assessment and communication. When a gene variant does not follow a classic Mendelian pattern of inheritance, featuring reduced penetrance, risk estimates for a condition are most often probabilities. Typically, population or empirical data are the beginning point to consider for an a priori genetic risk. For neurodegenerative disorders like PD, these are typically observed data in a population across an interval of time, and often will be expressed as a cumulative risk of disease to a specific age17.

Table 3 Established monogenic PD genes (ordered alphabetically and by inheritance)a.
Table 4 Important genetic terms for PD risk communication.

Another consideration is that variants in the same gene may have a different penetrance1. The use of up-to-date, accurate population data for a specific gene variant is vital for calculating risk estimates. When using penetrance data, note that data ascertainment, sample sizes, and population biases may erode quality of the data17. Another limitation of the data is that it is not entirely clear how various demographic features modulate PD genetic risks such as ancestral background or gender. Another limitation is that some penetrance data, especially for GBA1, are based on case-control studies providing only odds ratios (ORs). If used, ORs and relative risks (RR) should be converted to absolute risk estimates for the patient18.

Family histories are invaluable in that they may provide additional clues as to how variants have been expressed in a particular family, add insight into the potential for other shared factors, providing personalized risks. As of yet, risk calculators for neurodegenerative disorders such as PD are not widely available for clinical use to combine all the different factors, genetic and non genetic, that contribute to an individual person’s overall risk for disease18. Various algorithms such as PREDICT-PD and prodromal criteria have been developed19,20, focusing on early clinical features of PD, which may inform counseling as the tools become more refined and are able to incorporate more genetic data including data from non-European populations.

Complexities related to types of positive genetic test results

PD genetic test results can be complicated, depending on the type of result. For instance, there has been the observation that carriers of autosomal recessive variants may have a slightly increased risk for later-onset PD; however, research continues in this area and conclusions are mixed21,22. In the meantime, it can be conveyed that there is not a definite answer regarding risk to those carrying an autosomal recessive PD gene variant, but, if confirmed, is likely of low magnitude and of later onset.

Generally, when two pathogenic PD variants are identified, this is consistent with autosomal recessive inheritance. However, another complexity, similar to that of other autosomal recessive genetic disorders, is whether the variants are on the same (cis) or different (trans) chromosomes, since this is not typically revealed by genetic testing. Determining the phase, cis or trans, is important since a cis phase would mean that both variants are on the same chromosome and inherited from one parent, versus trans where each chromosome in the pair would have a variant, with one variant copy inherited from each parent. If phase of the variants cannot be readily determined by clinical information, this would be important to clarify with additional testing of parents/other affected family members since it will impact the recurrence risks provided.

Another complex type of PD result is copy number variants such as rare gene duplications and triplications of the SNCA gene and deletions and duplications commonly observed for the PRKN gene. Providers may be less familiar with these types of gene variants; however, these unique variants follow the same Mendelian rules for monogenic disease1.

Finally, the vast number of pathogenic gene variants (400+), and the potential for recombinant alleles, reported for the GBA1 gene pose their own challenges to risk communication, requiring special attention. Some of these rarer variants have limited empirical data from which to base risk estimates7. For most GBA1 variants, there is the association with Gaucher disease, an autosomal recessive lysosomal disorder that can manifest in childhood or be present unknowingly in mildly expressing adults and be amenable to treatment9. For a few GBA1 variants, some quite commonly carried, such as the E326K variant, this is not the case: Gaucher disease is not caused by carrying biallelic GBA1 variants, even though the variant is thought to be associated with PD23. This additional aspect of the GBA1 gene, namely its association with Gaucher disease, impact on reproductive risk, and potential medical action, requires added time to discuss and creates complexity to risk communication9.

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