Germline Genetic Risk Variants for Progressive Multifocal Leukoencephalopathy

Area of Science:

• Neuroimmunology
• Infectious Diseases
• Genetics

Background:

• Progressive multifocal leukoencephalopathy (PML) is a rare, severe demyelinating brain disorder caused by JC virus (JCV) reactivation.
• PML primarily affects immunocompromised individuals, including those with HIV, hematological malignancies, or on immunosuppressive therapies like natalizumab for multiple sclerosis (MS).
• Current JCV antibody testing for natalizumab users is suboptimal due to low specificity and the need for repeat testing.

Purpose of the Study:

• To identify host genetic risk variants for PML.
• To develop a genetic risk prediction test for PML, independent of JCV serostatus.
• To assess the potential of a genetic test to prevent PML cases in at-risk populations, particularly MS patients considering natalizumab.

Main Methods:

• Exome sequencing was performed on 185 PML cases (70 in discovery, 115 in replication cohorts).
• The gnomAD variant database was used for variant interpretation.
• Identified rare variants impacting immune function genes were modeled for a genetic risk prediction test.

Main Results:

• Nineteen rare variants (MAF ≤ 0.02) impacting 17 immune function genes were identified.
• Ten of these genes are associated with known inborn errors of immunity.
• Modeling suggests at least 25% of PML cases in MS patients on natalizumab could be preventable with a genetic risk test.

Conclusions:

• Host genetic variants contribute to PML susceptibility.
• A one-time genetic risk prediction test could offer valuable, independent risk assessment for PML.
• Genetic testing may enable proactive management and potentially prevent a significant proportion of PML cases.