首页期刊导航|中华医学遗传学杂志
期刊信息/Journal information
中华医学遗传学杂志
四川大学
中华医学遗传学杂志

四川大学

张思仲

双月刊

1003-9406

cjmg@cma.org.cn

028-85501165

610041

四川省成都市人民南路三段17号(四川大学华西校区)

中华医学遗传学杂志/Journal Chinese Journal of Medical GeneticsCSCD北大核心CSTPCD
查看更多>>中华医学会主办，四川大学承办。本刊以报道我国医学遗传学、人类遗传学和相关领域的基础理论、技术方法等最新研究成果；以从事医学遗传学工作的各科临床医生、计划生育工作者、大专院校和科研单位有关人员为主要读者对象。设有述评、论著、技术与方法、综述、调查报告、遗传咨询、临床细胞遗传学、病例报告等栏目。 从1998年以来被美国《医学索引》（IM）、《化学文摘》（CA）、《工程索引》（EI）、ISI数据库的Biological Abstracts及BIOSIS Previews，波兰《哥白尼索引》（IC）,荷兰《医学文摘》（EM）和俄罗斯《文摘杂志》（AJ）等国际著名检索系统收录。
正式出版
收录年代

    凝血因子Ⅻ缺乏症患者 F12基因的变异分析及分子机制探讨

    房帅杨嘉张夏林杨林花...
    429-434页
    查看更多>>摘要：目的 对20例凝血因子Ⅻ(FⅫ)缺乏症患者进行F12基因的测序分析并探讨其分子机制。 方法 选择2020年7月至2022年1月期间就诊于山西医科大学第二医院门诊部的20例FⅫ缺乏症患者作为研究对象。采用一期法检测其凝血因子Ⅷ(FⅧ：C)、Ⅸ(FⅨ：C)、Ⅺ(FⅪ：C)和Ⅻ(FⅫ：C)的活性。用Sanger测序对其F12基因的14个外显子以及5′和3′非翻译区进行分析，确定其变异位点。用生物信息学软件预测变异的致病性、分析氨基酸的保守性并模拟变异蛋白的模型。 结果 20例患者的FⅫ：C介于0.07% ~ 20.10%之间，远低于正常参考值，其他凝血指标则均未见异常。Sanger测序共发现10人携带F12基因的变异，具体包括4例错义变异[c.820C>T(p.Arg274Cys)、c.1561G>A(p.Glu521Lys)、c.181T>C(p.Cys61Arg)和c.566.G>C(p.Cys189Ser)]，4例缺失变异c.303_304delCA(p.His101GlnfsX36)，1例插入变异c.1093_1094insC(p.Lys365GlnfsX69)以及1例无义变异c.1763C>A(p.Ser588*)。其余10人仅检测出46C/T变异。其中，c.820C>T(p.Arg274Cys)杂合错义变异以及c.1763C>A(p.Ser588*)纯合无义变异未见临床遗传变异数据库和人类基因突变数据库收录。生物信息学分析提示，p.Arg274Cys与p.Ser588*均为致病变异，相关的氨基酸位点在不同物种中高度保守。蛋白预测模型提示，p.Arg274Cys破坏了原有氢键作用力，同时侧链变短，可影响FⅫ蛋白二级结构的稳定性，使关键的结构域发生变化。p.Ser588*导致FⅫ蛋白C端截短，改变了蛋白质结构的空间构象，可能影响丝氨酸蛋白酶的切割位点，导致FⅫ：C极度降低。 结论 在一期法检出的FⅫ：C偏低的患者中，50%携带F12基因的变异，其中c.820C>T错义变异和c.1763C>A无义变异是导致凝血因子Ⅻ减低的新的变异。 Objective To analyze the sequence of the F12 gene and molecular mechanism for 20 patients with coagulation factor Ⅻ (FⅫ) deficiency. Methods The patients were selected from the outpatient department of the Second Hospital of Shanxi Medical University from July 2020 to January 2022. The activity of coagulation factor Ⅷ (FⅧ: C), factor Ⅸ (FⅨ: C), factor Ⅺ (FⅪ: C) and factor Ⅻ (FⅫ: C) were determined by using a one-stage clotting assay. All exons and 5′ and 3′ UTR of the F12 gene were analyzed by Sanger sequencing to detect the potential variants. Bioinformatic software was used to predict the pathogenicity of the variants, conservation of amino acids, and protein models. Results The FⅫ: C of the 20 patients has ranged from 0.07% to 20.10%, which was far below the reference values, whilst the other coagulation indexes were all normal. Sanger sequencing has identified genetic variants in 10 patients, including 4 with missense variants [c.820C>T (p.Arg274Cys), c. 1561G>A (p.Glu521Lys), c. 181T>C (p.Cys61Arg) and c. 566.G>C (p.Cys189Ser)], 4 deletional variants c. 303_304delCA(p.His101GlnfsX36), 1 insertional variant c. 1093_1094insC (p.Lys365GlnfsX69) and 1 nonsense variant c. 1763C>A (p.Ser588*). The remaining 10 patients only harbored the 46C/T variant. The heterozygous c. 820C>T(p.Arg274Cys) missense variant in patient 1 and the homozygous c. 1763C>A (p.Ser588*) nonsense variant in patient 2 were not included in the ClinVar and the Human Gene Mutation Database. Bioinformatic analysis predicted that both variants were pathogenic, and the corresponding amino acids are highly conserved. The protein prediction models suggested that the c. 820C>T (p.Arg274Cys) variant may affect the stability of the secondary structure of FⅫ protein by disrupting the original hydrogen bonding force and truncating the side chain, leading to changes in the vital domain. c. 1763C>A (p.Ser588*) may produce a truncated C-terminus which may alter the spatial conformation of the protein domain and affect the serine protease cleavage site, resulting in extremely reduced FⅫ: C. Conclusion Among individuals with low low FⅫ: C detected by one-stage clotting assay, 50% have harbored variants of the F12 gene, among which the c. 820C>T and c. 1763C>A were novel variants underlying the reduced coagulating factor FⅫ.

    Ⅻ因子缺乏Ⅻ因子F12基因基因变异

      原文链接:
    • 万方数据

    急性髓系白血病患者表观遗传学修饰基因突变的分析

    魏计锋仇惠英周航陈泽...
    435-441页
    查看更多>>摘要：目的 探讨急性髓系白血病(AML)患者表观遗传学修饰基因突变(EMMs)的携带率及其临床特征。 方法 选取2011年5月至2021年2月于连云港市第一人民医院初诊的172例AML患者为研究对象。应用二代测序技术检测42种髓系基因的变异情况，回顾性分析EMMs患者的临床及分子学特征，以及去甲基药物(HMAs)对其生存的影响。 结果 在172例初诊的AML患者中，71例(41.28%)携带EMMs [EMMs(+)]，变异基因分别为TET2(14.53%，25/172)、DNMT3A(11.63%，20/172)、ASXL1(9.30%，16/172)、IDH2(9.30%，16/172)、IDH1(8.14%，14/172)、EZH2(0.58%，1/172)。EMMs(+)患者的外周血血红蛋白低于EMMs(-)患者(72 g/L vs. 88 g/L，Z＝-1.985，P<0.05)。老年AML患者的EMMs(+)携带率显著高于青年患者[71.11%(32/45)vs. 30.70%(39/127)，χ2 ＝ 22.38，P<0.001]。EMMs与NPM1基因变异呈正相关(r＝0.413，P<0.001)，与CEPBA基因双变异呈负相关(r＝-0.219，P<0.05)。EMMs(+)的预后中危AML患者中，与常规化疗方案相比，含HMAs的化疗方案可以延长患者中位无进展生存时间(PFS)及中位总生存时间(OS)(PFS：11.5个月vs. 25.5个月，P<0.05；OS：12.5个月vs. 27个月，P<0.05)。在老年患者中，与常规方案相比，含HMAs化疗方案也可延长中位PFS及中位OS(PFS：4个月vs. 18.5个月，P<0.05；7个月vs. 23.5个月，P<0.05)。 结论 AML患者的EMMs携带率较高，含HMAs的化疗方案可以延长预后中危及老年AML患者的生存，对AML的个体化治疗有一定的指导意义。 Objective To investigate the carrier rate and clinical characteristics of epigenetic modification gene mutations (EMMs) among patients with acute myeloid leukemia (AML). Methods One hundred seventy two patients who were initially diagnosed with AML at the First People′s Hospital of Lianyungang from May 2011 to February 2021 were selected as the study subjects. Next-generation sequencing was carried out to detect variants of 42 myeloid genes among these patients. Clinical and molecular characteristics of patients with EMMs and the effect of demethylation drugs (HMAs) on their survival were analyzed. Results Among the 172 AML patients, 71 (41.28%) were found to harbor the EMMs, and carrier rates were TET2 (14.53%, 25/172), DNMT3A (11.63%, 20/172), ASXL1 (9.30%, 16/172), IDH2 (9.30%, 16/172), IDH1 (8.14%, 14/172), EZH2 (0.58%, 1/172). Patients with EMMs (+ ) had lower peripheral hemoglobin compared with those with EMMs (-) (72 g/L vs. 88 g/L, Z=-1.985, P<0.05). The proportion of EMMs(+ ) among elderly AML patients was significantly higher than that of young AML patients [71.11% (32/45)vs. 30.70% (39/127), χ2 = 22.38, P < 0.001]. EMMs (+ ) were significantly correlated with NPM1 gene variants (r=0.413, P < 0.001), while negatively correlated with CEPBA double variants (r=-0.219, P<0.05). Compared with conventional chemotherapy regimens, HMAs-containing chemotherapy regimens have improved the median progression-free survival (PFS) and median overall survival (OS) among intermediate-risk AML patients with EMMs (+ ) (PFS: 11.5 monthsvs. 25.5 months, P<0.05 12.5 monthsvs. 27 months, P<0.05). Similarly, Compared with conventional chemotherapy regimens, chemotherapy with HMAs had increased median PFS and median OS in elderly AML patients with EMMs(+ ) (4 monthsvs. 18.5 months, P<0.05 7 monthsvs. 23.5 months, P<0.05). Conclusion Patients with AML have a high rate of EMMs carriage, and HMAs-containing chemotherapy regimens can prolong the survival of elderly patients with AML with poor prognosis, which may provide a reference for individualized treatment.

    急性髓系白血病表观遗传学修饰基因突变去甲基化药物疗效

      原文链接:
    • 万方数据

    产前染色体微阵列分析结果为新发临床意义不明变异胎儿的随访结果

    顾雷雷刘威周春香曹培暄...
    442-445页
    查看更多>>摘要：目的 探讨产前染色体微阵列分析(CMA)结果为新发临床意义不明变异(VOUS)胎儿的临床预后。 方法 以2017年7月至2021年12月在南京大学医学院附属鼓楼医院产前诊断中心接受检测的6 826例胎儿为研究对象。回顾性分析其CMA检测的结果，对判定为新发VOUS的胎儿进行随访。 结果 在6 826例胎儿中，506例为VOUS，其中237例进行了溯源检测，24例为新发变异。有效随访20例，随访时间范围为出生后4 ~ 26个月，其中4例引产，4例出生后出现临床表型，12例未见异常。 结论 建议对VOUS进行溯源检测，并对携带新发VOUS的胎儿进行持续随访，以明确VOUS的临床意义。 Objective To analyze the prognosis of fetuses identified with de novo variants of unknown significance (VOUS) by chromosome microarray analysis (CMA). Methods A total of 6 826 fetuses who underwent prenatal CMA detection at the Prenatal Diagnosis Center of Drum Tower Hospital from July 2017 to December 2021 were selected as the study subjects. The results of prenatal diagnosis, and outcome of fetuses identified with VOUS of de novo origin were followed up. Results Among the 6 826 fetuses, 506 have carried VOUS, of which 237 were detected for the parent-of-origin and 24 were found to be de novo. Among the latters, 20 were followed up for 4 to 24 months. Four couples had opted elective abortion, 4 had developed clinical phenotypes after birth, and 12 were normal. Conclusion Fetuses with VOUS should be continuously follow-up, in particular those carrying de novo VOUS, in order to clarify their clinical significance.

    染色体微阵列分析临床意义不明变异新发变异胎儿

      原文链接:
    • 万方数据

    自然流产患者1 065例的遗传学病因及其相关因素的分析

    丁虎段红蕾朱湘玉刘威...
    446-451页
    查看更多>>摘要：目的 探讨1 065例自然流产患者的遗传学病因及其相关因素。 方法 选择2018年1月至2021年12月于南京鼓楼医院产前诊断中心就诊的1 065例自然流产患者为研究对象。采集患者的绒毛组织或胎儿皮肤组织，用染色体微阵列分析(CMA)对其基因组DNA进行检测。选取10对CMA检测未见异常的非体外受精-胚胎移植(IVF-ET)妊娠、既往无活产分娩史且无子宫结构畸形的早期复发性流产夫妇，采集其外周静脉血样，进行家系全外显子组测序(trio-WES)，并通过Sanger测序对结果进行验证，并对候选变异进行生物信息学分析。采用多因素非条件Logistic回归分析法，对可能影响流产组织中染色体异常的因素进行分析，包括夫妇双方的年龄、既往自然流产的次数、是否进行IVF-ET以及有无活产分娩史等。不同流产次数的低龄和高龄患者早期流产组织染色体非整倍体发生率的比较采用线性趋势χ2检验。 结果 在1 065份自然流产组织中，CMA共检出染色体异常570例(53.5%)，其中染色体非整倍体489例(45.9%)，致病/可疑致病拷贝数变异(CNVs)36例(3.4%)。在10对夫妇中，trio-WES检测在2对夫妇的流产组织中分别发现1个纯合变异和1个复合杂合变异，均遗传自亲代；在2对夫妇的自然流产组织中分别发现1个疑似致病变异。多因素非条件Logistic回归分析显示，孕妇年龄是流产组织染色体异常的独立风险因素(OR ＝ 1.122，95%CI：1.069-1.177，P<0.001)，既往流产次数和IVF-ET妊娠则是其独立保护因素(OR ＝ 0.791、0.648，95%CI：0.682-0.916、0.500-0.840，P＝0.002、0.001)，配偶年龄和活产分娩史并非其独立风险因素(P>0.05)。在低龄患者的流产组织中，非整倍体的发生率随既往自然流产次数的增加而下降(χ2 ＝ 18.051，P<0.001)。在高龄患者的流产组织中，非整倍体的发生率则与既往自然流产的次数无显著相关性(P>0.05)。 结论 自然流产的遗传学病因以染色体非整倍体为主，而CNVs与基因变异也值得重视。孕妇的年龄、既往流产的次数及IVF-ET妊娠与流产组织中的染色体异常密切相关。 Objective To explore the genetic etiology and related factors in 1 065 women with spontaneous abortions. Methods All patients have presented at the Center of Prenatal Diagnosis of Nanjing Drum Tower Hospital from January 2018 to December 2021. Chorionic villi and fetal skin samples were collected, and the genomic DNA was assayed by chromosomal microarray analysis (CMA). For 10 couples with recurrent spontaneous abortions but normal CMA results for abortive tissues, non-in vitro fertilization-embryo transfer (IVF-ET) pregnancies and no previous history of live births and no structural abnormalities of the uterus, peripheral venous blood samples were collected. Genomic DNA was subjected to trio-whole exome sequencing (trio-WES). Candidate variants were verified by Sanger sequencing and bioinformatics analysis. Multifactorial unconditional logistic regression analysis was carried out to analyze the factors that may affect chromosomal abnormality in spontaneous abortions, such as the age of the couple, number of previous spontaneous abortions, IVF-ET pregnancy and history of live birth. The incidence of chromosomal aneuploidies in spontaneous abortions during the first trimester was compared in young or advanced-aged patients by chi-square test for liner trend. Results Among the 1 065 spontaneous abortion patients, 570 cases (53.5%) of chromosomal abnormalities were detected in spontaneous abortion tissues, which included 489 cases (45.9%) of chromosomal aneuploidies and 36 cases (3.4%) of pathogenic/likely pathogenic copy number variations (CNVs). Trio-WES results have revealed one homozygote variant and one compound heterozygote variants in two pedigrees, both of which were inherited from the parents. One likely pathogenic variant was detected in the patient from two pedigrees. Multifactorial unconditional Logistic regression analysis suggested that age of patient was an independent risk factor of chromosome abnormalities (OR = 1.122, 95%CI: 1.069-1.177, P<0.001), the number of previous abortions and IVF-ET pregnancy were independent protective factors for chromosomal abnormalities (OR = 0.791, 0.648 95%CI: 0.682-0.916, 0.500-0.840 P=0.002, 0.001), whilst the age of husband and history of live birth were not (P>0.05). The incidence of aneuploidies in the abortive tissues has decreased with the number of previous spontaneous abortions in young patients (χ2 = 18.051, P<0.001), but was not significantly correlated with the number of previous spontaneous abortions in advanced-aged patients with spontaneous abortions (P>0.05). Conclusion Chromosomal aneuploidy is the main genetic factor for spontaneous abortion, though CNVs and genetic variants may also underlie its genetic etiology. The age of patients, number of previous abortions and IVF-ET pregnancy are closely associated with chromosome abnormalities in abortive tissues.

    自然流产染色体微阵列分析拷贝数变异全外显子组测序影响因素

      原文链接:
    • 万方数据

    黏多糖贮积症ⅢA型一个家系的遗传学分析

    左汉恒李银平崔英华张金国...
    452-457页
    查看更多>>摘要：目的 探讨1例以肥厚型心肌病为首发表现的黏多糖贮积症ⅢA型(MSP ⅢA)患者的临床及遗传学特征。 方法 选取2022年1月就诊于济宁医学院附属医院的1例MPS ⅢA先证者及其家系成员(3代共7人)作为研究对象。收集先证者的临床资料，采集先证者及其家系成员的外周血样，进行全外显子组测序，对候选变异进行Sanger测序家系验证。同时根据变异位点的相关疾病进行硫酸乙酰肝素硫酸酯酶的活性检测。 结果 先证者为49岁女性，心脏MRI提示左室壁明显增厚，最厚处近20 mm，钆延迟增强扫描心尖部心肌局部延迟强化。全外显子组测序发现患者SGSH基因存在c.545G>A(p.Arg182His)/c.703G>A(p.Asp235Asn)复合杂合变异。Sanger测序提示其母亲携带c.545G>A(p.Arg182His)杂合变异，父亲、姐姐、妹妹和儿子均携带c.703G>A(p.Asp235Asn)杂合变异。依据美国医学遗传学与基因组学学会(ACMG)相关指南，c.545G>A及c.703G>A均评级为致病性变异(PM2_Supporting +PM3+PP1_Strong+PP3+PP4；PS3+PM1+PM2_Supporting +PM3+PP3+PP4)。患者外周血白细胞乙酰肝素-N-硫酸酯酶活性明显偏低，为1.6 nmol/(g·h)。父亲、母亲、姐姐、妹妹和儿子检测均未见异常。 结论 SGSH基因复合杂合变异可能是先证者MPS ⅢA的遗传学病因，心肌肥厚为相关的临床表型。 Objective To explore the clinical and genetic characteristics of a patient with hypertrophic cardiomyopathy as the initial manifestation of Mucopolysaccharidosis type Ⅲ A(MPS ⅢA). Methods A female patient with MPS Ⅲ A who was admitted to the Affiliated Hospital of Jining Medical University in January 2022 and her family members (seven individuals from three generations) were selected as the study subjects. Clinical data of the proband were collected. Peripheral blood samples of the proband was collected and subjected to whole exome sequencing. Candidate variants were verified by Sanger sequencing. Heparan-N-sulfatase activity was determined for the disease associated with the variant site. Results The proband was a 49-year-old woman, for whom cardiac MRI has revealed significant thickening (up to 20 mm) of left ventricular wall and delayed gadolinium enhancement at the apical myocardium. Genetic testing revealed that she has harbored compound heterozygous variants in exon 17 of the SGSH gene, namely c. 545G>A (p.Arg182His) and c. 703G>A (p.Asp235Asn). Based on guidelines from the American College of Medical Genetics and Genomics(ACMG), both variants were predicted to be pathogenic (PM2_Supporting + PM3+ PP1Strong+ PP3+ PP4 PS3+ PM1+ PM2_Supporting + PM3+ PP3+ PP4). Sanger sequencing confirmed that her mother was heterozygous for the c. 545G>A (p.Arg182His) variant, whilst her father, sisters and her son were heterozygous for the c. 703G>A (p.Asp235Asn) variant. Determination of blood leukocyte heparan-N-sulfatase activity suggested that the patient had a low level of 1.6 nmol/(g·h), whilst that of her father, elder and younger sisters and son were all in the normal range. Conclusion The compound heterozygous variants of the SGSH gene probably underlay the MPS ⅢA in this patient, for which hypertrophic cardiomyopathy is an associated phenotype.

    黏多糖累积病Ⅲ型SGSH基因全外显子组测序肥厚型心肌病家系

      原文链接:
    • 万方数据

    产前诊断ins(10；13)(q11.2；q31q33)mat染色体异常1例

    江淼孔祥东许芯李岭...
    457页
    查看更多>>摘要：患者 女，34岁，G3P2，表型及智力未见异常，于2017年8月5日因"继发不孕症"来郑州大学第一附属医院就诊。遗传咨询后夫妇双方进行外周血染色体检查，患者核型为46，XX, ins(10；13)(q11.2；q31q33)(图1)，患者丈夫核型未见异常。患者要求通过植入前遗传学检测技术进行辅助生殖，成功受孕后，于孕16+4周时进行低深度全基因组拷贝数变异测序(copy number variation sequencing，CNV-seq)和染色体核型分析，胎儿CNV-seq分析结果未见异常，胎儿的核型分析结果为46，XX，ins(10；13)(q11.2；q31q33)mat(图2)。本研究通过了郑州大学第一附属医院伦理委员会的审查(KS-2018-KY-36)，夫妻双方均签署了临床研究知情同意书。
      原文链接:
    • 万方数据

    LDLR基因变异所致家族性高胆固醇血症患者1例的遗传学分析

    王冠雄刘丽婷高阳吕明荣...
    458-461页
    查看更多>>摘要：目的 探讨1例家族性高胆固醇血症(FH)患者LDLR基因的变异特点，为其临床诊断与遗传咨询提供依据。 方法 选取2020年6月于安徽医科大学第一附属医院生殖中心就诊的1例FH患者为研究对象。收集患者的临床资料，应用全外显子组测序(WES)对患者进行基因检测，应用Sanger测序对候选变异进行家系验证，查阅UCSC数据库进行变异位点保守性分析。 结果 患者的临床表现为血清总胆固醇水平升高，其中低密度脂蛋白胆固醇显著升高。WES结果显示患者LDLR基因存在c.2344A>T(p.Lys782*)杂合变异，既往未见报道。Sanger测序验证该变异为父源性，患者父亲LDLR基因存在c.2344A>T(p.Lys782*)杂合变异，患者母亲该位点为野生型。查询UCSC数据库提示该变异位点高度保守。 结论 LDLR基因c.2344A>T杂合变异可能为该FH患者的遗传学病因。本研究为该家系的遗传咨询和产前诊断提供了依据。 Objective To analyze variant of LDLR gene in a patient with familial hypercholesterolemia (FH) in order to provide a basis for the clinical diagnosis and genetic counseling. Methods A patient who had visited the Reproductive Medicine Center of the First Affiliated Hospital of Anhui Medical University in June 2020 was selected as the study subject. Clinical data of the patient was collected. Whole exome sequencing (WES) was applied to the patient. Candidate variant was verified by Sanger sequencing. Conservation of the variant site was analyzed by searching the UCSC database. Results The total cholesterol level of the patient was increased, especially low density lipoprotein cholesterol. A heterozygous c. 2344A>T (p.Lys782*) variant was detected in theLDLR gene. Sanger sequencing confirmed that the variant was inherited from the father. Conclusion The heterozygous c. 2344A>T(p.Lys782*) variant of theLDLR gene probably underlay the FH in this patient. Above finding has provided a basis for genetic counseling and prenatal diagnosis for this family.

    家族性高胆固醇血症LDLR基因全外显子组测序基因变异

      原文链接:
    • 万方数据

    CYP11B2/CYP11B1融合基因致11β羟化酶缺乏症1例的遗传学分析

    林一凡杨海花袁淑娴李东晓...
    462-467页
    查看更多>>摘要：目的 探讨1例CYP11B2/CYP11B1融合基因所致11β羟化酶缺乏症(11β-OHD)患儿的遗传学特征，并为其父母提供产前遗传咨询。 方法 选取1例2020年8月24日就诊于河南省儿童医院内分泌科的患儿为研究对象。收集患儿临床资料，采集患儿及其父母的外周血样，对患儿进行全外显子组测序(WES)，对候选变异进行Sanger测序家系验证。用RT-PCR及Long-PCR确定患儿的融合基因。 结果 患儿为5岁男性，第二性征发育提前，生长加速，诊断为21羟化酶缺乏症(21-OHD)。WES检测提示患儿CYP11B1基因存在杂合错义变异c.1385T>C(p.L462P),同时染色体8q24.3区存在37.02 kb的杂合缺失。根据美国医学遗传学与基因组学学会(ACMG)相关指南，将c.1385T>C(p.L462P)评级为可能致病变异(PM2_Supporting+PP3_Moderate+PM3+PP4)。RT-PCR及Long-PCR联合检测结果提示为CYP11B1和CYP11B2基因重组，形成CYP11B2 exon 1~7/CYP11B1 exon 7~9融合基因。患儿被确诊为11β-OHD，经氢化可的松及曲普瑞林治疗有效。患儿父母经遗传咨询后娩1个健康后代。 结论 因CYP11B2/CYP11B1融合基因所致的11β-OHD易被误诊为21-OHD，需采用多种基因检测手段联合进行诊断。 Objective To analyze a child with 11β hydroxylase deficiency (11β-OHD) due toCYP11B2/CYP11B1 chimeric gene. Methods Clinical data of the child who was admitted to Henan Children′s Hospital on August 24, 2020 were retrospectively analyzed. Peripheral blood samples of the child and his parents were collected and subjected to whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing. RT-PCR and Long-PCR were carried out to verify the presence of chimeric gene. Results The patient, a 5-year-old male, had featured premature development of secondary sex characteristics and accelerated growth, and was diagnosed with 21 hydroxylase deficiency(21-OHD). WES revealed that he has harbored a heterozygous c. 1385T>C (p.L462P) variant of theCYP11B1 gene, in addition to a 37.02 kb deletion on 8q24.3. Based on the guidelines from the American College of Medical Genetics and Genomics(ACMG), the c. 1385T>C (p.L462P) was rated as a likely pathogenic variant (PM2_Supporting+ PP3_Moderate+ PM3+ PP4). The results of RT-PCR and Long-PCR suggested thatCYP11B1 and CYP11B2 genes have recombined to form a CYP11B2 exon 1~7/CYP11B1 exon 7~9 chimeric gene. The patient was diagnosed as 11β-OHD and effectively treated with hydrocortisone and triptorelin. A healthy fetus was delivered following genetic counseling and prenatal diagnosis. Conclusion 11β-OHD may be misdiagnosed as 21-OHD due to the potentialCYP11B2/CYP11B1 chimeric gene, which will require multiple methods for the detection.

    类固醇11-β-羟化酶11β羟化酶缺乏症CYP11B1基因CYP11B2/CYP11B1融合基因儿童

      原文链接:
    • 万方数据

    COL11A1基因变异所致罕见纤维软骨增生症患儿1例的遗传学分析

    李丹阳张钏周秉博陈雪...
    468-472页
    查看更多>>摘要：目的 探讨1例纤维软骨增生1型(FBCG1)患儿的临床表型及遗传学特征。 方法 选取2021年1月21日因"重症肺炎、疑似先天性遗传代谢病"就诊于甘肃省妇幼保健院的1例FBCG1患儿作为研究对象。收集患儿的临床资料，提取患儿及其父母的外周血样DNA，进行全外显子组测序(WES)，用Sanger测序对候选变异进行家系验证。 结果 患儿为1月龄女性，存在面部畸形、骨骼发育异常及四肢内翻等表型。WES检测显示其携带COL11A1基因c.3358G>A/c.2295+1G>A复合杂合变异，相关疾病为纤维软骨增生症。上述变异分别遗传自表型正常的父亲和母亲。根据美国医学遗传学与基因组学学会(ACMG)相关指南，c.3358G>A变异符合判读PM1+PM2_Supporting+PM3+PP3，c.2295+1G>A变异符合判读PVS1+PM2_Supporting，二者均被判定为可能致病性变异。 结论 COL11A1基因c.3358G>A/c.2295+1G>A复合杂合变异可能是患儿的遗传学病因。上述发现对患儿的确诊、遗传咨询及其父母的再生育指导具有重要的意义。 Objective To analyze the clinical data and genetic characteristics of a child with fibrocartilage hyperplasia type 1 (FBCG1). Methods A child who was admitted to Gansu Provincial Maternity and Child Health Care Hospital on January 21, 2021 due to severe pneumonia and suspected congenital genetic metabolic disorder was selected as the study subject. Clinical data of the child was collected, and genomic DNA was extracted from peripheral blood samples from the child and her parents. Whole exome sequencing (WES) was carried out, and candidate variants were verified by Sanger sequencing. Results The patient, a 1-month-old girl, had presented with facial dysmorphism, abnormal skeletal development, and clubbing of upper and lower limbs. WES revealed that she has harbored compound heterozygous variants c. 3358G>A/c.2295+ 1G>A of theCOL11A1 gene, which has been associated with fibrochondrogenesis. Sanger sequencing has verified that the variants have been respectively inherited from her father and mother, both of whom were phenotypically normal. Based on the guidelines from the American College of Medical Genetics and Genomics(ACMG), the c. 3358G>A variant was graded as likely pathogenic (PM1+ PM2_Supporting+ PM3+ PP3), and so was the c. 2295+ 1G>A variant (PVS1+ PM2_Supporting). Conclusion The compound heterozygous variants c. 3358G>A/c.2295+ 1G>A probably underlay the disease in this child. Above finding has facilitated definite diagnosis, genetic counseling for her family.

    纤维软骨COL11A1基因纤维软骨增生症全外显子组测序基因变异儿童

      原文链接:
    • 万方数据

    早发性重度肥胖患儿1例的临床及遗传学分析

    王萍萍杨素红周琼张建美...
    473-477页
    查看更多>>摘要：目的 探讨1例早发性重度肥胖患儿的临床特征与遗传学病因。 方法 选取2020年8月5日就诊于杭州市儿童医院内分泌科的1例早发性重度肥胖患儿为研究对象。收集患儿的临床资料，采集患儿及其父母的外周静脉血样，对患儿进行全外显子组测序(WES)，用Sanger测序对候选变异进行家系验证，并对其进行生物信息学分析。 结果 患儿为女性，2岁9月龄，临床表现为重度肥胖、颈部与腋下皮肤有色素沉积。WES检测结果提示，患儿携带MC4R基因c.831T>A(p.Cys277*)和c.184A>G(p.Asn62Asp)复合杂合变异。经Sanger测序验证分别遗传自其父亲和母亲。生物信息学分析：(1)MC4R基因c.831T>A(p.Cys277*)变异已被ClinVar数据库收录；检索1000 Genomes、ExAC及gnomAD数据库，该变异在正常东亚人群中的携带频率为0.000 4。根据美国医学遗传学与基因组学学会(ACMG)相关指南，评级为致病性变异。(2)MC4R基因c.184A>G(p.Asn62Asp)变异在ClinVar、1000 Genomes、ExAC及gnomAD数据库中均未见收录；经SIFT与PolyPhen-2等在线软件分析，均预测为有害变异。根据ACMG相关指南评级为疑似致病性变异。 结论 MC4R基因c.831T>A(p.Cys277*)和c.184A>G(p.Asn62Asp)复合杂合变异可能是早发性重度肥胖患儿的遗传学病因。上述发现丰富了MC4R基因的变异谱，为该患儿的临床诊断与遗传咨询提供了依据。 Objective To explore the clinical phenotype and genetic etiology of a child with early-onset severe obesity. Methods A child who presented at the Department of Endocrinology, Hangzhou Children′s Hospital on August 5, 2020 was selected as the study subject. Clinical data of the child were reviewed. Genomic DNA was extracted from peripheral blood samples of the child and her parents. Whole exome sequencing (WES) was carried out on the child. Candidate variants were verified by Sanger sequencing and bioinformatic analysis. Results This child was a 2-year-and-9-month girl featuring severe obesity with hyperpigmentation on the neck and armpit skin. WES revealed that she has harbored compound heterozygous variants of the MC4R gene, namely c. 831T>A (p.Cys277*) and c. 184A>G (p.Asn62Asp). Sanger sequencing confirmed that they were respectively inherited from her father and mother. The c. 831T>A (p.Cys277*) has been recorded by the ClinVar database. Its carrier frequency among normal East Asians was 0.000 4 according to the 1000 Genomes, ExAC, and gnomAD databases. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), it was rated as pathogenic. The c. 184A>G (p.Asn62Asp) has not been recorded in the ClinVar, 1000 Genomes, ExAC and gnomAD databases. Prediction using IFT and PolyPhen-2 online software suggested it to be deleterious. Based on the guidelines from the ACMG, it was determined as likely pathogenic. Conclusion The c. 831T>A (p.Cys277*) and c. 184A>G (p.Asn62Asp) compound heterozygous variants of theMC4R gene probably underlay the early-onset severe obesity in this child. Above finding has further expanded the spectrum of MC4R gene variants and provided a reference for the diagnosis and genetic counseling for this family.

    重度肥胖MC4R基因复合杂合变异全外显子组测序

      原文链接:
    • 万方数据