Fig. 6: Graphical abstract.

This graphical abstract illustrates the proposed pathways linking somatic expansion and its effects on biomarkers in HD-YAS. Inherited CAG repeat length is identified as the primary driver of disease progression in HD⁵⁷. Red arrows represent observed data associations in HD-YAS and blue arrows reflect assumed causal relationships. The black bidirectional arrow under mechanisms indicates somatic expansion in WBCs as a proxy for CNS expansion, based on shared inherited genetic modifiers^14,17. The black bidirectional arrow under biomarkers shows associations between elevated CSF NfL (marker of neuroaxonal damage) and reduced CSF PENK (surrogate of striatal MSN state) with the earliest caudate and putamen volume changes. Somatic expansion is influenced by inherited CAG repeat length, age and DNA mismatch repair gene variants^14,17. DNA mismatch repair, highlighted in the schematic and shown as a repeat loop-out mismatch icon, is a key mechanism linking inherited CAG repeat length to somatic expansion¹⁶ with repair activity increasing with longer CAG repeat lengths⁵⁸. Within the CNS, somatic expansions substantially contribute to disease progression, as supported by recent postmortem research⁸. While brain biopsy would be the gold standard for direct assessment of CNS somatic expansion in vivo, WBC-derived somatic expansion is detectable peripherally, showing early and longitudinal changes by HD-ISS stages 0 and 1. The biomarkers section shows associations of somatic expansion with the earliest caudate and putamen volume changes, and CSF NfL and PENK levels. The age continuum from HD-ISS stage 0 to stage 1 illustrates early detection of somatic expansion and biomarker changes, influencing pathology from stage 0 onward. HD-YAS provides in vivo evidence that somatic expansion drives early pathology during these early stages, highlighting its potential as a promising therapeutic target in proof-of-concept clinical trials at HD-ISS stages 0 and 1 to slow or prevent further neurodegeneration before clinical motor diagnosis. WBC, white blood cell. The figure is created with BioRender.com.