Nagaoka Shinichi, Yamaguchi-Kabata Yumi, Shiga Naomi, Tachibana Masahito, Yasuda Jun, Tadaka Shu, Tamiya Gen, Fuse Nobuo, Kinoshita Kengo, Kure Shigeo, Murotsuki Jun, Yamamoto Masayuki, Yaegashi Nobuo, Sugawara Junichi
Graduate School of Medicine, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.
Tokyo Metropolitan Ohtsuka Hospital, 2-8-1, Minami-ohtsuka, Toshima-ku, Tokyo, 170-8476, Japan.
Hum Genome Var. 2021 Jan 15;8(1):2. doi: 10.1038/s41439-020-00133-7.
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.
骨发育异常是一组罕见的遗传性疾病，多达436种疾病类型。围产期诊断对于充分的个性化管理和咨询在临床上具有重要意义。目前尚无针对一般人群中骨发育异常致病变异的报道。在本研究中，我们聚焦于常染色体隐性骨发育异常。我们使用来自3552名日本个体的全基因组参考面板数据来识别致病变异。首次，我们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异常，我们检测到54个致病基因的198个致病变异。我们估计了与四种临床上重要的骨发育异常相关变异的携带者频率和潜在患者比例，这四种骨发育异常分别为成骨不全（OI）、低磷酸酯酶症（HPP）、窒息性胸廓发育不良（ATD）和埃利斯-范克里夫德综合征（EvC）。基于InterVar分类为“致病”和“可能致病”的致病变异，OI、ATD和EvC的潜在患者比例更接近日本受试者中报道的发病率。此外，InterVar分类为“致病”和“可能致病”且ClinVar分类为“致病”的HPP变异的潜在患者比例更接近报道的发病率。对于骨发育异常，本研究的结果将有助于更好地了解日本一般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。
