Estimation of the carrier frequencies and proportions of potential patients by detecting causative gene variants associated with autosomal recessive bone dysplasia using a whole-genome reference panel of Japanese individuals.
Estimation of the carrier frequencies and proportions of potential patients by detecting causative gene variants associated with autosomal recessive bone dysplasia using a whole-genome reference panel of Japanese individuals.
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DOI：
10.1038/s41439-020-00133-7
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发表时间：
2021-01-15
影响因子：
1.5
通讯作者：
Sugawara J
中科院分区：
文献类型：
--
作者：
Nagaoka S;Yamaguchi-Kabata Y;Shiga N;Tachibana M;Yasuda J;Tadaka S;Tamiya G;Fuse N;Kinoshita K;Kure S;Murotsuki J;Yamamoto M;Yaegashi N;Sugawara J
骨发育不良是一组罕见的遗传性疾病，疾病类型多达436种。围产期诊断对于充分的个性化管理和咨询具有重要的临床意义。目前还没有针对普通人群骨发育不良致病变异的报道。在这项研究中，我们关注常染色体隐性遗传性骨发育不良。我们使用 3552 名日本人的全基因组参考组数据鉴定了致病变异。我们第一次能够估计携带者频率和潜在患者的比例。对于常染色体隐性骨发育不良，我们检测到 54 个致病基因的 198 个致病变异。我们估计了变异携带者频率以及携带与四种临床上重要的骨发育不良相关的变异的潜在患者的比例：成骨不全症（OI）、低磷酸酯酶症（HPP）、窒息性胸廓发育不良（ATD）和Ellis-van Creveld综合征（EvC）。根据 InterVar 分类为“致病”和“可能致病”的致病变异，潜在 OI、ATD 和 EvC 患者的比例更接近日本受试者报告的发病率。此外，InterVar 中被分类为“致病”和“可能致病”以及 ClinVar 中被分类为“致病”的潜在 HPP 变异患者的比例更接近报告的发病率。对于骨发育不良，这项研究的结果将有助于更好地了解日本普通人群中的变异类型和频率，并且应该对临床诊断、遗传咨询和个性化医疗有用。生物信息学方法有助于估计一种罕见的遗传性骨病的携带频率，这种疾病会导致骨骼形状和结构异常。常染色体隐性骨发育不良会影响骨骼和软骨的发育，是由于遗传了两个突变基因（父母各一个）所致。日本仙台东北大学的 Junichi Sukawara 及其同事使用突变数据库和用于变异解释的生物信息学工具，在 3,552 名普通日本人的全基因组参考组 (3.5KJPNv2) 中检测了与常染色体隐性骨发育不良相关的 54 个基因中的 198 个致病变异。然后，他们估计了样本中携带骨发育不良突变的人群的频率以及可能出现这种疾病的预期比例，这与报告的一般人群的发病率进行了很好的比较。这些发现可能有助于计算携带者父母未来孩子骨发育不良的风险。
Bone dysplasias are a group of rare hereditary diseases, with up to 436 disease types. Perinatal diagnosis is clinically important for adequate personalized management and counseling. There are no reports focused on pathogenic variants of bone dysplasias in the general population. In this study, we focused on autosomal recessive bone dysplasias. We identified pathogenic variants using whole-genome reference panel data from 3552 Japanese individuals. For the first time, we were able to estimate the carrier frequencies and the proportions of potential patients. For autosomal recessive bone dysplasias, we detected 198 pathogenic variants of 54 causative genes. We estimated the variant carrier frequencies and the proportions of potential patients with variants associated with four clinically important bone dysplasias: osteogenesis imperfecta (OI), hypophosphatasia (HPP), asphyxiating thoracic dysplasia (ATD), and Ellis–van Creveld syndrome (EvC). The proportions of potential patients with OI, ATD, and EvC based on pathogenic variants classified as “pathogenic” and “likely pathogenic” by InterVar were closer to the reported incidence rates in Japanese subjects. Furthermore, the proportions of potential patients with HPP variants classified as “pathogenic” and “likely pathogenic” in InterVar and “pathogenic” in ClinVar were closer to the reported incidence rates. For bone dysplasia, the findings of this study will provide a better understanding of the variant types and frequencies in the Japanese general population, and should be useful for clinical diagnosis, genetic counseling, and personalized medicine. A bioinformatics approach helps estimate carrier frequency of a rare inherited bone disease which causes abnormalities in skeletal shape and structure. Autosomal recessive bone dysplasias affect bone and cartilage development and result from inheriting two mutated genes, one from each parent. Junichi Sugawara, Tohoku University, Sendai, Japan, and colleagues used mutation databases and a bioinformatics tool for variant interpretation to detect 198 pathogenic variants in 54 genes associated with autosomal recessive bone dysplasia in a whole-genome reference panel of 3,552 general Japanese individuals (3.5KJPNv2). They then estimated the frequency of people in the sample carrying bone dysplasia mutations and the expected proportion in whom the disorder could manifest, which compared well with reported incidence rates in the general population. These findings could prove useful for calculating the risk of bone dysplasia in the future children of carrier parents.
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