The Genetic and Phenotypic Spectrum of Primary Brain Calcification in a Large Cohort from China

Primary brain calcification (PBC) is a monogenic inherited disease characterized by calcifications in basal ganglia and other brain regions, with seven causative genes identified and highly heterogeneous genetic and phenotypic spectrum.

The objective was to update the genetic and phenotypic spectrum of PBC in a large cohort from China.

Five hundred eighty-four PBC families were enrolled. Brain calcification was assessed by total calcification score (TCS). Sanger sequencing of SLC20A2 and whole-exome sequencing were performed. Variants were classified by the American College of Medical Genetics and Genomics guidelines.

Eighty-eight probands were genetically diagnosed with pathogenic or likely pathogenic variants in SLC20A2 (75.86%), PDGFRB (2.30%), PDGFB (3.45%), XPR1 (3.45%), MYORG (11.49%), JAM2 (3.45%), and NAA60 (1.15%). Totally, 29 unreported variants were detected. Autosomal recessive PBC (AR-PBC) patients exhibited a higher rate of clinical symptoms compared to those with autosomal dominant PBC (AD-PBC) (100.00% vs. 55.06%, P < 0.001). In all PBC, advancing age showed associations with headache/dizziness (odds ratio [OR] = 0.97, P = 0.0241), cognitive dysfunction (OR = 1.07, P = 0.0025), and psychiatric symptoms (OR = 1.05, P = 0.0396). Regional calcification analysis showed that thalamic calcification scores were associated with cognitive impairment (OR = 1.34, P = 0.0026), followed by lenticular nucleus calcification with headache/dizziness (OR = 1.55, P = 0.0046), cerebellar hemisphere calcification with motor symptoms (OR = 1.45, P = 0.0051), and caudate nucleus calcification with psychiatric manifestations (OR = 1.2, P = 0.0351).

This large-scale Chinese cohort study demonstrates the genetic spectrum of PBC and phenotypic characteristics in genetically diagnosed PBC, and also provides genotype-imaging-symptom correlations of PBC. © 2025 International Parkinson and Movement Disorder Society.