Identification of pathogenic variants in three Chinese patients with McCune-Albright syndrome
韩明辰 1米欢 1管鑫 1任秀智 2赵秀丽 1李岭
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作者信息
1. 1中国医学科学院基础医学研究所 北京协和医学院基础学院医学遗传学系，北京 100005
2. 2天津市武清区人民医院骨外科，天津 301799
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摘要
目的 对3例McCune-Albright综合征(MAS)患者进行候选基因GNAS的变异鉴定，以明确其遗传学病因。 方法 选取2019年4月于山东省立医院就诊和2020年8月、2021年5月于北京协和医院就诊的共3例患者为研究对象。采用酚-氯仿法提取患者及其家系成员的外周血样基因组DNA，通过全外显子组测序(WES)对候选致病变异进行筛查，通过Sanger测序对候选变异进行家系验证。 结果 测序显示家系1患者存在GNAS基因第8外显子的c.601C>T(p.Arg201Cys)杂合错义变异；家系2和家系3患者均存在GNAS基因第8外显子的c.602G>A(p.Arg201His)杂合错义变异。两种变异均为已知致病变异，患者均为相应致病变异的嵌合体，但比例有所不同。 结论 WES是鉴定MAS等体细胞遗传病的有效方法。本研究联合应用WES和Sanger测序鉴定了MAS患者致病变异及其嵌合程度，并证实其与患者的表型无明显相关性，为遗传咨询和产前诊断提供了依据。 Objective To explore the genetic basis for three Chinese patients with McCune-Albright syndrome (MAS). Methods Three children who visited Shandong Provincial Hospital in April 2019 and Peking Union Medical College Hospital in August 2020 and May 2021 were selected as the research subjects. Peripheral blood samples of the probands and their family members were taken for the extraction of genomic DNA. Potential variants were screened by whole exome sequencing (WES), and candidate variants were validated by Sanger sequencing of the patients and their family members. Results The proband from family 1 was found to harbor a heterozygous c. 601C>T (p.R201C) missense variant in exon 8 of theGNAS gene, whilst the probands from families 2 and 3 were both found to harbor a heterozygous c. 602G>A (p.R201H) missense variant in exon 8 of theGNAS gene. Both variants were known to be pathogenic, and all probands were found to be mosaics for the corresponding variants but with various degrees. Conclusion WES can effectively diagnose MAS and other somatic genetic disorders. In this study, the combined WES and Sanger sequencing have verified the degree of mosaicisms of pathogenic variants in the three MAS patients, albeit no apparent correlation was found between the degree of mosaicisms and the phenotype of patients. Above finding has provided a basis for genetic counseling and prenatal diagnosis for the affected families.
Abstract
Objective To explore the genetic basis for three Chinese patients with McCune-Albright syndrome (MAS). Methods Three children who visited Shandong Provincial Hospital in April 2019 and Peking Union Medical College Hospital in August 2020 and May 2021 were selected as the research subjects. Peripheral blood samples of the probands and their family members were taken for the extraction of genomic DNA. Potential variants were screened by whole exome sequencing (WES), and candidate variants were validated by Sanger sequencing of the patients and their family members. Results The proband from family 1 was found to harbor a heterozygous c. 601C>T (p.R201C) missense variant in exon 8 of theGNAS gene, whilst the probands from families 2 and 3 were both found to harbor a heterozygous c. 602G>A (p.R201H) missense variant in exon 8 of theGNAS gene. Both variants were known to be pathogenic, and all probands were found to be mosaics for the corresponding variants but with various degrees. Conclusion WES can effectively diagnose MAS and other somatic genetic disorders. In this study, the combined WES and Sanger sequencing have verified the degree of mosaicisms of pathogenic variants in the three MAS patients, albeit no apparent correlation was found between the degree of mosaicisms and the phenotype of patients. Above finding has provided a basis for genetic counseling and prenatal diagnosis for the affected families.
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