SLC20A2 Intragenic Structural Variants as a Cause of Primary Brain Calcification
Wen-Hao Xiao1,2,3, Dan-Dan Zuo1,2,3, Ze-Hong Zheng1,2,3
1Department of Neurology, Fujian Institute of Neurology, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
Background:
Intragenic structural variants of SLC20A2 remain poorly characterized in primary brain calcification (PBC).
Objectives:
The aim was to identify and characterize intragenic SLC20A2 structural variants in PBC.
Methods:
One familial PBC pedigree and two sporadic patients underwent whole-genome sequencing and copy-number analysis, followed by polymerase chain reaction (PCR) and Sanger validation. Long-read sequencing (LRS) resolved complex architecture. Transcript and protein effects were assessed by reverse transcription (RT)-PCR, RT-quantitative PCR, and western blotting.
Results:
We identified three intragenic SLC20A2 structural variants: exon 2-3 and exon 5 tandem duplications in F1 and F3, respectively, and a complex exon 2-3 inverted insertion in F2. F1 and F3 showed aberrant, frameshift-generating transcripts, and F3 showed reduced SLC20A2 mRNA and protein. Accordingly, the F1 and F3 variants were classified as pathogenic, whereas the F2 variant remained of uncertain significance.
Conclusions:
Our study expands the spectrum of intragenic SLC20A2 structural variation in PBC and highlights the value of copy number variation analysis and LRS in genetically unresolved individuals. © 2026 International Parkinson and Movement Disorder Society.
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