Objective: To delineate the genetic landscape of progressive supranuclear palsy (PSP) in Chinese patients.Progressive supranuclear palsy is a neurodegenerative disorder primarily considered sporadic, with MAPT as the major risk gene in Caucasians. While recent Southeast Asian studies identified MAPT, GBA1, and SQSTM1 as key contributors, genetic data from East Asian populations remain limited.

Background: Progressive supranuclear palsy is a neurodegenerative disorder primarily considered sporadic, with MAPT as the major risk gene in Caucasians. While recent Southeast Asian studies identified MAPT, GBA1, and SQSTM1 as key contributors, genetic data from East Asian populations remain limited.

Method: Next-generation sequencing (whole-exome, whole-genome, and targeted sequencing) was conducted in 40 Chinese PSP patients. A curated panel of 26 PSP-related genes was established through systematic literature review. Variants were classified into four tiers: pathogenic/likely pathogenic (P/LP) in PSP-related genes, variants of uncertain significance (VUS) in PSP-related genes, P/LP variants in genes linked to neurodegenerative diseases but not yet associated with PSP, and others.

Results: Pathogenic or likely pathogenic variants consistent with their respective inheritance patterns were detected in 20% (8/40) of patients: three carried PSP-related variants (CCNF, DCTN1, POLG), while five harbored variants in neurodegeneration genes linked to PSP-like phenotypes (AARS1, TDP1, FA2H, TBP, ATXN8). Notably, no MAPT pathogenic variants or C9orf72 repeat expansions were observed, contrasting with Southeast Asian cohorts where MAPT variants occurred in familial cases. Among five patients (12.5%) with family histories, one carried a AARS1 P/LP variant (Tier 3), while three exhibited VUS (Tier 2) in PSEN1, SQSTM1, and POLG.

Conclusion: This first Chinese PSP genetic study reveals a population-specific variant profile distinct from both Caucasian and Southeast Asian cohorts, with novel associations between PSP and leukoencephalopathy-related AARS1 variants. The absence of MAPT involvement and enrichment of non-PSP neurodegeneration genes underscore the need for ethnic-specific diagnostic frameworks. These findings advocate for expanded Asian cohort studies to refine PSP genetic architectures and optimize clinical screening strategies.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/identification-of-genetic-variants-in-progressive-supranuclear-palsy-in-china/