A De Novo 16p13.3 Triplication Underlying Early-Onset Complex Neurodegeneration.
TL;DR
These findings support a role for structural variation in early-onset neurodegeneration and highlight the value of combining short-read copy-number profiling with long-read WGS to detect and characterize complex genomic rearrangements.
Abstract
Background
Neurodegenerative disorders are clinically and genetically heterogeneous, characterized by progressive neuronal loss and multidomain functional decline. Despite a presumed genetic etiology, a substantial proportion of cases remain molecularly undiagnosed.
Objective
The aim was to identify the genetic cause of an early-onset neurodegenerative disorder presenting with ataxia and cognitive impairment.
Methods
Rare copy-number variants were detected via short-read whole-genome sequencing (WGS), with candidate structural models inferred using long-read WGS. We performed transcriptomic profiling of peripheral blood leukocytes by RNA sequencing, with validation using reverse transcription-quantitative polymerase chain reaction (RT-qPCR).
Results
We identified a de novo copy-number gain at 16p13.3. Combined copy-number profiling and long-read WGS suggested a candidate model comprising a triplicated segment in tandem with a proximal duplication, joined to a distal duplication via an inverted junction. Transcriptomic analysis demonstrated significant upregulation of ATP6V0C, AMDHD2, and PDPK1.
Conclusions
These findings support a role for structural variation in early-onset neurodegeneration and highlight the value of combining short-read copy-number profiling with long-read WGS to detect and characterize complex genomic rearrangements. © 2026 International Parkinson and Movement Disorder Society.