Parkinson’s disease (PD) is typically multifactorial, and many of the gene variants have incomplete penetrance and variable expression.
Guidelines for medical and family history intake
Intake should include specific clinical information on both the patient and key relatives including: (1) age of onset and/or diagnosis, (2) related neurologic or neurodegenerative conditions, and (3) prior genetic testing for the patient or family members.
Early deaths, adoptions, and small family structures should be documented as this can result in under ascertainment of cases when doing risk assessment.
Ethnicity of the family on both maternal and paternal sides should be noted, including Ashkenazi Jewish ancestry.
Important factors to consider during PD risk assessment
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3-4% lifetime risk in general population (GeneReviews)
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Overall, idiopathic PD is more common in males.
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Late-onset PD is considered to be multifactorial in most cases.
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Early-onset PD (EOPD, or YOPD; when diagnosed <50 years old) is more likely to be genetic, and more likely to follow autosomal recessive inheritance.
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With increasing age, the risk of PD increases.
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10-15% of PD is familial.
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The lifetime risk of PD increases to 6-8% if an individual has a family member with PD; however, with a family history suggesting autosomal dominant or autosomal recessive inheritance, the individual’s lifetime risk can be even higher than that (based on discovered or undiscovered genes).
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Relevant family history can include PD or related conditions (essential tremor, parkinsonism, dementia with Lewy bodies [LBD], progressive supranuclear palsy [PSP], corticobasal syndrome [CBS], multiple system atrophy [MSA]), or Gaucher disease.
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Individuals without a family history have been reported to have a genetic variant.
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Reduced penetrance & variable expressivity in PD genetics can affect risk assessment.
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Any ancestry can have a genetic variant.
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Ancestry impacts risk of developing PD, depending on the variant.
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Founder variants are known in Ashkenazi Jewish (GBA1, LRRK2), North African Berber and Spanish Basque (LRRK2), and Europeans (GBA1, other).
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After genetic testing, the risk counseling may be complicated by the reduced penetrance or variable expressivity seen in known variants.
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Specific values for penetrance can vary based on age, specific gene variants, ethnicity, and other risk factors.
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More comprehensive testing may be available if the testing was limited to DTC, single-gene, multi-site, or research only. DTC/research testing may only include specific variants, and some commercial panel testing may not include all genes or variants relevant to PD.
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A negative genetic test result does not entirely rule out a genetic contribution to disease.
*adapted from NSGC Neurogenetics Special Interest Group (SIG) Movement Disorder Working Group Parkinson’s disease Resource Toolkit
For information on specific gene and variant risk-associations please view our Parkinson's Disease Gene Penetrance resource.
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