Si Chen1, Zhidong Cen1, Feng Fu2, You Chen1, Xinhui Chen3, Dehao Yang1, Haotian Wang4, Hongwei Wu5, Xiaosheng Zheng6, Fei Xie7, Zhiyuan Ouyang4, Weiguo Tang8, Shuhong Zhang9, Lili Yin10, Yunqian Zhang11, Peiying Meng12, Xuzhen Zhu13, Hongwei Zhang14, Feifei Jiang15, Kaiyu Zhang16, Juping He17, Danhong Zhang18, Hanqiao Ming19, Daqiao Song20, Zhiping Zhou21, Yong Luo22, Qun Gu23, Yongkun Su24, Xinxiao Wu25, Haiyan Tang26, Chenglong Wu27, Weiqing Chen28, Jing-Yu Liu29, Wei Luo30. 1. Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. 2. Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Department of Neurology, Zhuji People's Hospital of Zhejiang Province, Shaoxing, Zhejiang, China. 3. Chu Kochen Honors College, Zhejiang University, Hangzhou, Zhejiang, China. 4. Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. 5. Department of Neurology, Lishui People's Hospital, Lishui, Zhejiang, China. 6. Department of Intensive Care Unit, Zhejiang Hospital, Hangzhou, Zhejiang, China. 7. Department of Neurology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. 8. Department of Neurology, Zhoushan Hospital, Zhoushan, Zhejiang, China. 9. Department of Neurology, Longyou People's Hospital, Quzhou, Zhejiang, China. 10. Department of Neurology, Sanmen People's Hospital, Taizhou, Zhejiang, China. 11. Department of Neurology, The Fourth Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China. 12. Department of Neurology, Zhuji Central Hospital, Shaoxing, Zhejiang, China. 13. Department of Neurology, Hangzhou Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang, China. 14. Department of Neurology, Affiliated Hospital of Shaoxing University, Shaoxing, Zhejiang, China. 15. Department of Neurology, Quzhou People's Hospital, Quzhou, Zhejiang, China. 16. Department of Neurology, Huangyan District Hospital of Traditional Chinese Medicine, Taizhou, Zhejiang, China. 17. Department of Neurology, Dongyang People's Hospital, Jinhua, Zhejiang, China. 18. Department of Neurology, Taizhou Central Hospital, Taizhou, Zhejiang, China. 19. Department of Neurology, Jiangshan People's Hospital, Quzhuo, Zhejiang, China. 20. Department of Neurology, Yiwu Hospital of Traditional Chinese Medicine, Jinhua, Zhejiang, China. 21. Department of Neurology, Taishun People's Hospital, Wenzhou, Zhejiang, China. 22. Department of Neurology, Jinhua Municipal Central Hospital, Jinhua, Zhejiang, China. 23. Department of Neurology, Huzhou First People's Hospital, Huzhou, Zhejiang, China. 24. Department of Neurology, Tianzhu People's Hospital, Qiandongnan Miao and Dong Autonomous Prefecture, Guizhou, China. 25. Department of Neurology, Qingyuan People's Hospital, Lishui, Zhejiang, China. 26. Department of Neurology, Huzhou Central Hospital, Huzhou, Zhejiang, China. 27. Department of Neurology, Shaoxing People's Hospital, Shaoxing, Zhejiang, China. 28. Department of Neurology, Xianju People's Hospital, Taizhou, Zhejiang, China. 29. Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China. 30. Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. Electronic address: luoweirock@zju.edu.cn.
Abstract
BACKGROUND: Primary familial brain calcification (PFBC) is a rare calcifying disorder of the brain with extensive clinical and genetic heterogeneity. Its prevalence is underestimated due to clinical selection bias (compared with symptomatic PFBC patients, asymptomatic ones are less likely to undergo genetic testing). METHODS: A total of 273 PFBC probands were enrolled in a multicenter retrospective cohort study by two different approaches. In Group I (nonsystematic approach), 37 probands diagnosed at our clinic were enrolled. In Group II (systematic approach), 236 probands were enrolled by searching the medical imaging databases of 50 other hospitals using specific keywords. Genetic testing of four genes known to be causative of autosomal dominant PFBC was performed in all probands using cDNA. All identified variants were further confirmed using genomic DNA and classified according to ACMG-AMP recommendations. RESULTS: Thirty-two variants including 22 novel variants were detected in 37 probands. Among these probands, 83.8% (31/37) were asymptomatic. Two probands with homozygous pathogenic SLC20A2 variants presented more severe brain calcification and symptoms. Based on the variant detection rate of probands in Group II, we extrapolated an overall minimal prevalence of PFBC of 6.6 per 1,000, much higher than previously reported (2.1 per 1000). CONCLUSIONS: We identified a higher proportion of genetically confirmed PFBC probands who were asymptomatic. These patients would be overlooked due to clinical selection bias, leading to underestimation of the disease prevalence. Considering that PFBC patients with biallelic variants had more severe phenotypes, this specific condition should be focused on in genetic counseling.
BACKGROUND:Primary familial brain calcification (PFBC) is a rare calcifying disorder of the brain with extensive clinical and genetic heterogeneity. Its prevalence is underestimated due to clinical selection bias (compared with symptomatic PFBCpatients, asymptomatic ones are less likely to undergo genetic testing). METHODS: A total of 273 PFBC probands were enrolled in a multicenter retrospective cohort study by two different approaches. In Group I (nonsystematic approach), 37 probands diagnosed at our clinic were enrolled. In Group II (systematic approach), 236 probands were enrolled by searching the medical imaging databases of 50 other hospitals using specific keywords. Genetic testing of four genes known to be causative of autosomal dominant PFBC was performed in all probands using cDNA. All identified variants were further confirmed using genomic DNA and classified according to ACMG-AMP recommendations. RESULTS: Thirty-two variants including 22 novel variants were detected in 37 probands. Among these probands, 83.8% (31/37) were asymptomatic. Two probands with homozygous pathogenic SLC20A2 variants presented more severe brain calcification and symptoms. Based on the variant detection rate of probands in Group II, we extrapolated an overall minimal prevalence of PFBC of 6.6 per 1,000, much higher than previously reported (2.1 per 1000). CONCLUSIONS: We identified a higher proportion of genetically confirmed PFBC probands who were asymptomatic. These patients would be overlooked due to clinical selection bias, leading to underestimation of the disease prevalence. Considering that PFBCpatients with biallelic variants had more severe phenotypes, this specific condition should be focused on in genetic counseling.