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

IF 7.6 1区医学 Q1 CLINICAL NEUROLOGY Movement Disorders Pub Date : 2025-04-19 DOI:10.1002/mds.30207

Zhiru Lin MD, Dehao Yang MD, PhD, Lebo Wang MD, Jiaxiang Li MD, Xinhui Chen MD, Nan Jin MD, Yixin Kang MD, Xinchen Wang MD, Feng Fu MD, Haotian Wang MD, PhD, Xiaosheng Zheng MD, Fei Xie MD, PhD, Zhidong Cen MD, PhD, Wei Luo MD, PhD

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Abstract

Background

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.

Objective

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

Methods

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.

Results

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).

Conclusion

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.

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中国一大队列原发性脑钙化的遗传和表型谱。

原发性脑钙化（PBC）是一种以基底节区和其他脑区钙化为特征的单基因遗传性疾病，有7个致病基因，遗传和表型谱高度异质性。目的：更新中国一大队列PBC的遗传和表型谱。方法入选584个PBC家庭。采用总钙化评分（TCS）评价脑钙化程度。对SLC20A2进行Sanger测序和全外显子组测序。变异是根据美国医学遗传学和基因组学学院的指导方针分类的。结果在SLC20A2（75.86%）、PDGFRB（2.30%）、PDGFB（3.45%）、XPR1（3.45%）、MYORG（11.49%）、JAM2（3.45%）和NAA60（1.15%）中，有88个先证基因被诊断为致病性或可能致病性变异。总共检测到29种未报告的变异。常染色体隐性PBC （AR-PBC）患者比常染色体显性PBC （AD-PBC）患者表现出更高的临床症状率（100.00%比55.06%,P < 0.001）。在所有PBC中，年龄增长与头痛/头晕（优势比[OR] = 0.97, P = 0.0241）、认知功能障碍（OR = 1.07, P = 0.0025）和精神症状（OR = 1.05, P = 0.0396）相关。区域钙化分析显示，丘脑钙化评分与认知功能障碍相关（OR = 1.34, P = 0.0026），其次是晶状核钙化伴头痛/头晕（OR = 1.55, P = 0.0046），小脑半球钙化伴运动症状（OR = 1.45, P = 0.0051），尾状核钙化伴精神症状（OR = 1.2, P = 0.0351）。结论这项大规模的中国队列研究显示了PBC的遗传谱和基因诊断PBC的表型特征，并提供了PBC基因型-成像-症状的相关性。©2025国际帕金森和运动障碍学会。

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来源期刊

Movement Disorders 医学-临床神经学

CiteScore

13.30

自引率

8.10%

发文量

371

审稿时长

12 months

期刊介绍： Movement Disorders publishes a variety of content types including Reviews, Viewpoints, Full Length Articles, Historical Reports, Brief Reports, and Letters. The journal considers original manuscripts on topics related to the diagnosis, therapeutics, pharmacology, biochemistry, physiology, etiology, genetics, and epidemiology of movement disorders. Appropriate topics include Parkinsonism, Chorea, Tremors, Dystonia, Myoclonus, Tics, Tardive Dyskinesia, Spasticity, and Ataxia.

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