SLC20A2
Intragenic Structural Variants as a Cause of Primary Brain Calcification
Wen‐Hao Xiao, Dan‐Dan Zuo, Ze‐Hong Zheng, Ya‐Fang Chen, Xin‐Xin Guo, Min‐Kun Fang, Xiang‐Ping Yao, Hui‐Zhen Su, Xue‐Wen Cheng, Ning Wang, Miao Zhao, Wan‐Jin Chen, Ling Fang, Jin‐Lan Li, Yi‐Heng Zeng Abstract
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.