Underestimated disease prevalence and severe phenotypes in patients with biallelic variants: A cohort study of primary familial brain calcification from China
Underestimated disease prevalence and severe phenotypes in patients with biallelic variants: A cohort study of primary familial brain calcification from China
复制标题
双等位基因变异患者的疾病患病率和严重表型被低估：中国原发性家族性脑钙化的队列研究
DOI：
10.1016/j.parkreldis.2019.04.009
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发表时间：
2019-07-01
影响因子：
4.1
通讯作者：
Zhang, Xiaoluo
中科院分区：
文献类型：
--
作者：
Chen, Si;Cen, Zhidong;Zhang, Xiaoluo
背景：原发性家族性脑钙化（PFBC）是一种罕见的脑钙化疾病，具有广泛的临床和遗传异质性。由于临床选择偏倚，其患病率被低估（与有症状的PFBC患者相比，无症状的患者较少接受基因检测）。方法：通过两种不同的方法，共纳入273名PFBC先证者进行多中心回顾性队列研究。在第一组（非系统方法）中，纳入了在我们诊所诊断的37名先证者。第二组（系统法）采用特定关键词检索其他50家医院的医学影像数据库，纳入236名先证者。利用cDNA对所有先证者进行常染色体显性PFBC的4个已知致病基因的基因检测。所有鉴定出的变异均使用基因组DNA进一步确认，并根据ACMG-AMP建议进行分类。结果：在37个先证者中检测到32个变异，其中新变异22个。在这些先证者中，83.8%（31/37）无症状。纯合致病性SLC20A2变异的2个先证者出现了更严重的脑钙化和症状。根据II组先证者的变异检出率，我们推断PFBC的总体最小患病率为6.6 / 1000，远高于之前报道的2.1 / 1000。结论：我们确定了更高比例的基因证实的PFBC先证者无症状。这些患者会因临床选择偏倚而被忽视，导致对疾病患病率的低估。考虑到双等位基因变异的PFBC患者具有更严重的表型，在遗传咨询中应重点关注这一特殊情况。
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.