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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。
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    孕中期甲状腺功能对胎儿游离DNA分数的影响

    张宇琼乔龙威王挺李岭...
    1191-1196页
    查看更多>>摘要：目的 探讨孕中期甲状腺功能与胎儿游离DNA分数(FF)的相关性。 方法 将1 861例于2016年1月至2020年12月就诊于南京医科大学附属苏州医院·苏州市立医院的孕妇作为研究对象，在孕12 ~ 26周对其进行无创产前检测(NIPT)以及甲状腺素功能检测。用单变量分析和多变量回归模型评估其游离甲状腺素(FT4)水平与FF的相关性。 结果 单因素线性回归分析表明，FF随FT4水平的升高而升高(b ＝ 0.035，P<0.001)，中位数为10.78%(IQR：8.2%，13.82%)，随着FT4从≤ 12.0 pmol/L增高至FT4 > 16.0 pmol/L，FF的中位数分别为10.58%(IQR：7.86%，13.30%)至11.77%(IQR：8.64%，15.30%)。在进一步校正孕周和身体质量指数后，FF随着FT4水平的升高呈现增加的趋势，且具有显著的统计学意义(Ptrend < 0.001)。 结论 孕妇的游离甲状腺素水平可在一定程度上影响胎儿游离DNA分数。 Objective To assess the influence of thyroid function on the fetal fraction (FF) during the second trimester of pregnancy. Methods A total of 1 861 pregnant women undergoing non-invasive prenatal testing (NIPT) and thyroxine function testing at 12 ~ 26 gestational weeks at the Affiliated Suzhou Hospital of Nanjing Medical University/Suzhou Municipal Hospital from January 2016 to December 2020 were selected as the study subjects. Univariate analysis and multivariate regression models were used to assess the correlation between free thyroxine 4 (FT4) levels and FF. Results Univariate linear regression analysis indicated that the FF is correlated to the level of FT4 (b = 0.035, P<0.001). The median fetal FF was 10.78% (IQR: 8.2%, 13.82%), and this has increased along with the level of FT4 from 10.58% at ≤ 12.0 pmol/L to 11.77% at > 16.0 pmol/L. After further adjustment of gestational age and body mass index (BMI), the FF showed an increase trend along with the increase of FT4 levels, and a trend test also showed a statistical significance (Ptrend < 0.001). Conclusion Maternal FF can be affected by the level of free thyroxine during the second trimester of pregnancy.

    无创产前检测胎儿游离DNA分数游离甲状腺素多变量线性回归模型

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    无创产前检测对于鉴定胎儿染色体数目结构异常及拷贝数变异的价值

    侯帅张昊晴李彩云陈丹婧...
    1197-1203页
    查看更多>>摘要：目的 探讨无创产前检测(NIPT)在胎儿染色体数目与结构异常及拷贝数变异(CNV)中的应用价值。 方法 选取2018年1月至2021年12月于郴州市第一人民医院产前诊断中心收治的46 197例孕妇为研究对象。采集孕妇外周血行NIPT，NIPT阳性孕妇经羊水细胞核型分析及拷贝数变异测序(CNV-seq)进一步鉴定，并分析3种检测结果的一致性。 结果 常见染色体非整倍体异常主要来自高龄孕妇，性染色体非整倍体异常主要来自高龄和血清学筛查临界风险或高风险孕妇，罕见常染色体非整倍体及CNV异常主要来自血清学筛查临界风险或高风险孕妇。NIPT检测胎儿染色体异常的阳性预测值(PPV)由高到低依次为：T21(92.37%，109/118)、T18(53.85%，14/26)、性染色体非整倍体(45.04%，59/131)、T13(34.62%，9/26)、CNV(29.17%，14/48)、罕见常染色体非整倍体(2.60%，2/77)。 结论 NIPT对于T21、T18、T13和性染色体非整倍体异常有较高的检出率，对于罕见常染色体非整倍体及CNV异常有一定的检测价值，能够提示一些染色体罕见结构异常，需要与羊水检测结果相互验证。 Objective To assess the value of non-invasive prenatal testing (NIPT) for the identification of numerical and structural chromosomal abnormalities and copy number variation (CNV) in fetuses. Methods 46 197 pregnant women undergoing NIPT at the Prenatal Diagnosis Center of Chenzhou First People′s Hospital from January 2018 to December 2021 were selected as the study subjects. Positive cases were subjected to chromosomal karyotyping and copy number variation sequencing (CNV-seq) following amniocentesis. Results Nearly 50% of common chromosomal aneuploidies were found in the elder pregnant women. Among these, sex chromosome aneuploidies were mainly found in pregnant women with advanced age as well as borderline risks by serological screening. Rare autosomal aneuploidies and CNV were mainly found in those with borderline or high risks by serological screening. The positive predictive values (PPV) for fetal chromosomal abnormalities indicated by NIPT were as follows: T21 (92.37%, 109/118), T18 (53.85%, 14/26), sex chromosome aneuploidies (45.04%, 59/131), T13 (34.62%, 9/26), CNV (29.17%, 14/48), and rare autosomal aneuploidies (2.60%, 2/77). Conclusion NIPT has a high detection rate for T21, T18, T13 and sex chromosome aneuploidies. It can also detect rare autosomal aneuploidies and CNV, including some rare structural abnormalities, though verification is required by analyzing amniotic fluid samples.

    无创产前检测染色体非整倍体拷贝数变异核型分析拷贝数变异测序

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    难治性癫痫患儿的基因变异特征分析

    王凯旋蔡丹丹盛放王大燕...
    1204-1210页
    查看更多>>摘要：目的 分析不同年龄段难治性癫痫(RE)患儿的基因变异特征，为精准诊疗提供一定的数据支撑。 方法 选取2018年1月1日至2019年11月21日于浙江大学医学院附属金华医院就诊的117例RE患儿为研究对象，根据发病年龄分为<1岁、1~<3岁、3~<12岁和≥12岁4组。回顾性分析患儿的临床资料、全外显子组测序数据、携带基因变异患儿的父母测序结果等资料。 结果 本研究纳入RE患者共117例，其中男性67例，女性50例。发病年龄范围为4日龄~14岁。117例RE患儿中，33例携带致病性或可能致病性变异，检出率为28.21%(33/117)。<1岁组、1~<3岁组和≥3岁组的检出率分别为53.85%(21/39)、12.00%(3/25)和16.98%(9/53)，差异有统计学意义(χ2＝19.202，P<0.001)。有、无共患病患儿的检出率分别为33.33%(12/36)和25.93%(21/81)，差异无统计学意义(χ2＝0.359，P＝0.549)。33例携带基因变异患儿中，27例为单核苷酸多态性变异(SNV)或插入缺失(InDel)变异，6例为拷贝数变异(CNV)。检出率最高的变异基因为PRRT2(15.15%，5/33)，其次为SCN1A(12.12%，4/33)。携带基因变异的患儿中，72.73%(8/11)的患儿根据参考文献调整药物后获得临床缓解。 结论 28.21%的RE患儿可检出致病或可能致病CNV变异，发病年龄小的患儿检出率较高，PRRT2和SCN1A基因受累较多见。根据受累基因的类型调整药物将有助于提高缓解率。 Objective To analyze the characteristics of genetic variants among children with refractory epilepsy (RE). Methods One hundred and seventeen children with RE who had presented at the Affiliated Jinhua Hospital of Zhejiang University School of Medicine from January 1, 2018 to November 21, 2019 were selected as the study subjects. The children were divided into four groups according to their ages of onset: < 1 year old, 1 ~ <3 years old, 3 ~ <12 years old, and ≥ 12 years old. Clinical data and results of trio-whole exome sequencing were retrospectively analyzed. Results In total 67 males and 50 females were included. The age of onset had ranged from 4 days to 14 years old. Among the 117 patients, 33 (28.21%) had carried pathogenic or likely pathogenic variants. The detection rates for the < 1 year old, 1 ~ <3 years old and ≥ 3 years old groups were 53.85% (21/39), 12.00% (3/25) and 16.98% (9/53), respectively, with a significant difference among the groups ( χ2 = 19.202, P < 0.001). The detection rates for patients with and without comorbidities were 33.33% (12/36) and 25.93% (21/81), respectively ( χ2 = 0.359, P = 0.549). Among the 33 patients carrying genetic variants, 27 were single nucleotide polymorphisms (SNPs) or insertion/deletion (InDel), and 6 were copy number variations (CNVs). The most common mutant genes were PRRT2 (15.15%, 5/33) and SCN1A (12.12%, 4/33). Among children carrying genetic variants, 72.73% (8/11) had attained clinical remission after adjusting the medication according to the references. Conclusion 28.21% of RE patients have harbored pathogenic or likely pathogenic variants or CNVs. The detection rates are higher in those with younger age of onset. PRRT2 and SCN1A genes are more commonly involved. Adjusting medication based on the types of affected genes may facilitate improvement of the remission rate.

    难治性癫痫儿童全外显子组测序单核苷酸多态性变异插入缺失变异拷贝数变异

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    原发性肥厚型心肌病患儿8例的临床表型及遗传学分析

    孙琪青王芳洁苏林博何坤...
    1211-1216页
    查看更多>>摘要：目的 探讨8例肥厚型心肌病(HCM)患儿的临床及遗传学特点。 方法 选取2018年1月至2021年12月河南省儿童医院心内科收治的8例HCM患儿作为研究对象，收集患儿的临床资料。对其中2例患儿采用单人全外显子组测序，6例患儿及其父母采用家系全外显子组测序。应用Sanger测序对患儿及其父母进行候选变异验证，并按照美国医学遗传学与基因组学学会(ACMG)相关变异标准与指南对变异进行致病性分析。 结果 8例患儿中，男5例，女3例，年龄在5个月~13岁之间，平均确诊年龄为(7.87±4.8)岁，心脏表型均提示非梗阻性HCM。基因检测提示4例患儿MYH7基因存在变异，分别为c.2155C>T(p.Arg719Trp)、c.1208G>A(p.Arg403Gln)、c.1358G>A(p.Arg453His)以及c.1498G>A(p.Glu500Lys)。依据ACMG相关变异评级指南，前3种变异均评级为致病性变异，c.1498G>A(p.Glu500Lys)评级为可能致病性变异(PM1＋PM2_Supporting＋PM6＋PP3)，既往未见报道。另4例患儿存在母源变异，其中MYL2：c.173G>A(p.Arg58Gln)评级为致病性变异，TPM1：c.574G>A(p.Glu192Lys)、ACTC1：c.301G>A(p.Glu101Lys)均评级为可能致病性变异，MYBPC3：c.146T>G(p.Ile49Ser)评级为意义未明。予以7例患儿0.5~3 mg/(kg·d)普萘洛尔治疗，症状明显好转，并随访至2022年9月30日未再发生心脏事件。 结论 对不明原因的心肌病进行基因检测可以明确其致病原因，为临床诊断提供依据，并为遗传咨询提供参考。MYH7基因变异c.1498G>A(p.Glu500Lys)的发现拓展了肥厚型心肌病基因变异谱。 Objective To explore the clinical and genetic characteristics of eight children with primary hypertrophic cardiomyopathy (HCM). Methods Eight children with HCM admitted to the Department of Cardiology of Henan Children′s Hospital from January 2018 to December 2021 were selected as the study subjects. Clinical data of the children were collected. Whole exome sequencing was carried out on two children, and trio whole exome sequencing was carried out on the remainder 6 children. Sanger sequencing was used to verify the candidate variants in the children and their parents, and the pathogenicity of the variants was evaluated based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). Results The patients had included 5 males and 3 females, with their ages ranging from 5 to 13 years old. The average age of diagnosis was (7.87 ± 4.8) years old, and the cardiac phenotype showed non-obstructive HCM in all of the patients. WES has identified variants of the MYH7 gene in 4 children, including c. 2155C>T (p.Arg719Trp), c. 1208G>A (p.Arg403Gln), c. 1358G>A (p.Arg453His), and c. 1498G>A (p.Glu500Lys). Based on the guidelines from the ACMG, the first 3 variants were classified as pathogenic, while c. 1498G>A (p.Glu500Lys) was classified as likely pathogenic (PM1+ PM2_Supporting+ PM6+ PP3), which was also unreported previously. The remaining four children had all harbored maternal variants, includingMYL2: c. 173G>A (p.Arg58Gln classified as pathogenic),TPM1: c. 574G>A (p.Glu192Lys) andACTC1: c. 301G>A (p.Glu101Lys) (both were classified as likely pathogenic), andMYBPC3: c. 146T>G (p.Ile49Ser classified as variant of uncertain significance). Seven children were treated with 0.5 ~ 3 mg/(kg·d) propranolol, and their symptoms had improved significantly. They were followed up until September 30, 2022 without further cardiac event. Conclusion Genetic testing can clarify the molecular basis for unexplained cardiomyopathy and provide a basis for clinical diagnosis and genetic counseling. Discovery of the c. 1498G>A (p.Glu500Lys) variant has also expanded the spectrum ofMYH7 gene mutations underlying HCM.

    心肌病,肥厚型MYH7基因致病性变异儿童

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    FKRP相关常染色体隐性遗传肢带型肌营养不良9型患者2例的临床特征及基因变异分析

    余婕徐敏丁乐黄艳军...
    1217-1221页
    查看更多>>摘要：目的 探讨FKRP相关常染色体隐性遗传肢带型肌营养不良9型(LGMD R9 FKRP-related)患者的基因型与表型的相关性。 方法 以2018年9月30日与2018年8月3日于南京医科大学附属儿童医院就诊的2例分别因心肌损害及肝功能损害就诊、经血清学检查为无症状的高磷酸肌酸激酶(CK)、疑似为进行性肌营养不良的患儿作为研究对象。收集患儿的临床资料，采集患儿及其父母的外周血样，进行全外显子组测序及Sanger测序家系验证。 结果 检测发现患儿1携带FKRP基因c.545A>G和c.941C>T复合杂合变异，二者均为已知变异，其中c.545A>G为中国人群中的热点变异；患儿2携带FKRP基因c.602T>C和c.961G>A复合杂合变异，二者既往均未见报道。 结论 结合2例患儿的临床特征及基因检测结果，确诊其为LGMD R9 FKRP-related。c.545A>G为中国人群LGMD R9FKRP-related的热点变异，携带者症状较轻。相较于携带恶性变异的患者，本研究2例患儿均携带FKRP基因复合杂合错义变异，其症状相对较轻，仅表现为无症状的高CK。 Objective To explore the correlation between clinical manifestations of limb-girdle muscular dystrophy autosomal recessive 9 FKRP-related(LGMD R9 FKRP-related) and variants of the FKRP gene. Methods Two children who had presented at the Children′s Hospital of Nanjing Medical University respectively due to increased serum myocardial zymogram and hepatic dysfunction on September 30, 2018 and August 3, 2018 were selected as the study subjects. Clinical data of the children were collected. Both children were suspected for Duchenne or Becker muscular dystrophy for asymptomatic high creatine kinase (CK) levels. Peripheral blood samples of the children and their parents were collected for whole exome sequencing, and candidate variants were validated by Sanger sequencing. Results Genetic testing revealed that both children have carried compound heterozygous variants of the FKRP gene. The c. 545A>G and c. 941C>T variants in child 1 have been reported previously, among which the c. 545A>G is a hot spot mutation in the Chinese population. Child 2 has carried c. 602T>C and c. 961G>A variants, both of which were unreported previously. Conclusion Both children have met the diagnostic criteria for LGMD R9 FKRP-related. Carriers of the c. 545A>G variant may present milder symptoms. Compared with patients carrying null variants, carriers of compound heterozygous missense variants may present with a milder phenotype, manifesting as asymptomatic high CK level.

    FKRP相关常染色体隐性遗传肢带型肌营养不良9型FKRP基因变异基因型表型

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    急性髓系白血病患者134例的基因变异特点

    何苗赵霄晨田红娟张姝婷...
    1222-1227页
    查看更多>>摘要：目的 探讨134例初诊急性髓系白血病(AML)患者的基因变异特点。 方法 回顾性分析2017年6月至2022年6月在联勤保障部队第九四〇医院初诊为AML(非急性早幼粒细胞白血病)134例患者的临床资料。基于二代测序进行AML相关基因检测，研究分析AML患者的变异频率及变异特点。本研究采用SPSS v26.0软件进行统计学处理，用似然比χ2检验和Fisher确切率法检验进行数据分析。 结果 134例患者中，男72例，女62例，男女比例为1.7：1，中位年龄51岁(9~86岁)。120例(76.1%)患者发生基因变异，26例(19.4%)患者为单基因变异，27例(20.1%)患者存在2个基因变异，49例(36.6%)患者同时携带≥3个基因变异；32例(23.9%)患者未检测到任何基因变异。134例患者总变异检出率在10%以上的变异基因依次为NPM1(n＝24，17.91%)、FLT3-ITD(n＝21，15.67%)、DNMT3A(n＝20，14.93%)、CEBPA单变异(n＝14，10.45%)、TET2(n＝14，10.45%)、NRAS(n＝14，10.45%)。根据染色体核型的不同将患者分为低危组、中危组和高危组，不同基因在不同染色体核型中的变异率不相同，19例低危组患者基因变异频率由高到低为NRAS(n＝4，21.05%)、KRAS(n＝4，21.05%)、KIT(n＝2，10.53%)；96例中危组基因变异频率由高到低为NPM1(n＝24，25.00%)、FLT3-ITD(n＝20，20.83%)、DNMT3A(n＝18，18.75%)、CEBPA(n＝12，12.50%)、TET2(n＝12，12.50%)；19例高危组基因变异频率由高到低依次为ASXL1(n＝7，21.05%)、NRAS(n＝3，15.97%)、TP53(n＝3，15.79%)、EZH2(n＝2，10.53%)，经统计学分析发现，KIT在低危组、NPM1、FLT3-ITD、DNMT3A在中危组、ASXL1在高危组的变异相对热点占比较高。 结论 AML患者基因变异频率较高，至少携带1个基因变异的患者大于76.1%，不同基因在不同的染色体核型患者中变异频率不一致，存在明显的优势变异，并且KIT、NPM1、FLT3-ITD、DNMT3A、ASXL1可以作为评估预后的因素之一。 Objective To analyze the characteristics of genetic variants in 134 patients diagnosed with Acute myeloid leukemia (AML). Methods Clinical data of the 134 patients with AML (non-acute promyelocytic leukemia) initially diagnosed at the 940th Hospital of the Joint Logistics Support Force of the Chinese People′s Liberation Army from June 2017 to June 2022 were retrospectively analyzed. Potential variants of AML-related genes were detected by next-generation sequencing, and the frequency of variants was analyzed by using SPSS v26.0 software, and likelihood ratio χ2 test and Fisher exact test were used for data analysis. Results The patients had included 72 males and 62 females, with a gender ratio of 1.7 : 1 and a median age of 51 years (9 ~ 86 years old). One hundred twenty patients (76.1%) had harbored at least one genetic variant, including 26 (19.4%) having a single variant, 27 (20.1%) having two variants, and 49 (36.6%) having ≥ 3 variants. 32 (23.9%) had no detectable variants. Genetic variants detected in over 10% of the 134 patients had included NPM1 (n = 24, 17.91%), FLT3-ITD (n = 21, 15.67%), DNMT3A (n = 20, 14.93%), CEBPA (single variant n = 14, 10.45%), TET2 (n = 14, 10.45%), and NRAS (n = 14, 10.45%). The patients were also divided into low risk, intermediate risk and high risk groups based on their chromosomal karyotypes. The mutational rates for genes in different groups have varied, with 19 patients from the low risk group harboring variants of NRAS (n = 4, 21.05%), KRAS (n = 4, 21.05%), and KIT (n = 2, 10.53%) and 96 patients from the intermediate risk group harboring variants of NPM1 (n = 24, 25.00%), FLT3-ITD (n = 20, 20.83%), DNMT3A (n = 18, 18.75%), CEBPA (n = 12, 12.50%), and TET2 genes (n = 12, 12.50%). The mutational frequencies for the 19 patients from the high risk group were ASXL1 (n = 7, 21.05%), NRAS (n = 3, 15.97%), TP53 (n = 3, 15.79%), and EZH2 (n = 2, 10.53%). A significant difference was found in the frequencies of KIT, NPM1, FLT3-ITD, DNMT3A, and ASXL1 gene variants among the low-risk, medium-risk, and high-risk groups. Conclusion AML patients have a high frequency for genetic variants, with 76.1% harboring at least one variant. The frequency of genetic variants have varied among patients with different chromosomal karyotypes, and there are apparent dominant variants. KIT, NPM1, FLT3-ITD, DNMT3A, and ASXL1 may be used as prognostic factors for evaluating their prognosis.

    急性髓系白血病基因变异二代测序变异频率

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    SLC6A4基因c.*670T>G多态性与壮族人群哮喘风险和外周血细胞特征的相关性

    陈高许建国韦帅蒙明虑...
    1228-1235页
    查看更多>>摘要：目的 探讨c.*670T>G与壮族人群哮喘风险和外周血特征的相关性。 方法 选取2017年5月至2020年3月于右江民族医学院附属医院和河池市人民医院就诊的258例哮喘患者与244名健康受试者为研究对象，使用重测序法鉴定c.*670T>G多态性以阐明基因型，流式细胞术结合电阻抗法对外周血细胞进行分类计数。 结果 研究对象的生活条件是平衡的。与T等位基因相比，G等位基因是壮族哮喘人群的遗传危险因素(OR＝1.54，95%CI＝1.15-2.06；P＝0.004)。与GT＋TT基因型相比，GG纯合基因型是壮族哮喘人群的遗传危险因素(OR＝1.66，95%CI＝1.16-2.38；P＝0.005)。风险因素分层后GG纯合基因型增加了男性和城市居民亚组人群患哮喘的风险(P<0.01)。哮喘组的红细胞、血红蛋白和血小板计数明显高于对照组(P<0.001)，血小板超过正常值的样本中GG基因型占比82.35%，GT基因型占比17.65%，无TT基因型的占比，GG基因型的血小板整体水平高于GT＋TT基因型(P<0.05)。显著性关联使用假阳性报告概率分析验证，在0.1的先验概率水平下，Gvs. T假阳性概率为0.071，GG vs.GT＋TT假阳性概率为0.153。 结论 c.*670T>G的GG基因型是广西西北部地区壮族人群哮喘的遗传危险因素，研究增加了c.*670T>G群体遗传的基因型和外周血表型的参考数据。 Objective To assess the association of SLC6A4 gene c. *670T>G polymorphism with the risk for asthma and peripheral blood cytological characteristics among ethnic Zhuang Chinese from Guangxi, China. Methods From May 2017 to March 2020, 258 patients diagnosed with asthma and 244 healthy controls were recruited from the Affiliated Hospital of Youjiang Minzhu Medical College and the People′s Hospital of Hechi. Genotypes of the c. *670T>G polymorphism were determined by Sanger sequencing. Flow cytometry was used in combination with an electrical impedance method for the counting and classification of peripheral blood cells. Results Compared with the T allele, the G allele of the c. *670T>G polymorphism was associated with the risk for asthma in the population (OR = 1.54, 95%CI = 1.15-2.06 P = 0.004). Compared with the GT and TT genotypes, homozygous GG genotype also comprised a risk factor (OR = 1.66, 95%CI = 1.16-2.38 P = 0.005). Stratification of the risk factors showed that the homozygous GG genotype has increased the risk of asthma in males and urban residents (P < 0.01). The erythrocyte, hemoglobin and platelet counts of the asthma group were significantly higher than the control group ( P < 0.001). The GG, GT and TT genotypes have respectively accounted for 82.35%, 17.65% and 0% of the samples with platelets exceeding the normal value. The overall platelet level of GG genotype was higher than GT+ TT genotype ( P < 0.05). The significant association was verified by the false positive report probability, and at a prior probability level of 0.1, G vs. T false positive probability was 0.071, and GG vs. GT+ TT false positive probability was 0.153. Conclusion The GG genotype of the c. *670T>G polymorphism is associated with the risk for asthma among ethnic Zhuang Chinese from northwest Guangxi. Above finding has also enriched the genotypic data and peripheral blood phenotype for this polymorphism.

    哮喘SLC6A4基因基因型表型血小板壮族地区

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    TMEM67基因变异致麦克尔综合征一个家系的遗传学分析

    赵干业赵晓燕赵学潮王聪慧...
    1236-1240页
    查看更多>>摘要：目的 探讨1个疑似麦克尔综合征家系的遗传学病因。 方法 选取2017年8月31日因"连续3次不良妊娠史"就诊于郑州大学第一附属医院的1个家系作为研究对象，收集家系相关临床资料。对该家系第3个引产胎儿组织通过高通量测序进行纤毛病相关致病基因变异筛选并用Sanger测序进行家系验证。 结果 该家系第1个胎儿妊娠过程中出现胚胎停育，第2个胎儿临床疑诊为纤毛病，后引产但未行进一步的病因检测，第3个胎儿疑诊为纤毛病且经高通量测序及Sanger测序检测，结果提示胎儿TMEM67基因存在父源的c.978＋1G>A和母源的c.1288G>C(p.D430H)复合杂合变异。依据美国医学遗传学与基因组学学会相关变异指南与标准，c.978＋1G>A评级为致病性变异(PVS1＋PM2_Supporting＋PP5)，c.1288G>C(p.D430H)评级为可能致病性变异(PM2_Supporting＋PM3＋PM5＋PP3)。 结论 TMEM67基因c.978＋1G>A和c.1288G>C(p.D430H)复合杂合变异应为该家系3次疑似纤毛病不良妊娠的遗传学病因。TMEM67基因c.1288G>C(p.D430H)变异的发现拓宽了TMEM67基因致病变异谱。 Objective To explore the genetic etiology for a Chinese pedigree affected with Meckel syndrome. Methods A pedigree with a history of three consecutive adverse pregnancies which presented at the First Affiliated Hospital of Zhengzhou University on August 31, 2017 was selected as the study subject. Clinical data of the pedigree were collected. High-throughput sequencing was carried out to screen for variants of ciliopathy-related genes in the third fetus following induced abortion, and candidate variant was verified by Sanger sequencing. Results The first pregnancy of the couple had ended as spontaneous abortion, whilst the fetus of the second pregnancy was suspected for having ciliopathy, though no genetic testing was carried out following elected abortion. The fetus of the third pregnancy was suspected for having ciliopathy, and high-throughput sequencing and Sanger sequencing had shown that the fetus had harbored compound heterozygous variants of the TMEM67 gene, including c. 978+ 1G>A from the father and c. 1288G>C (p.D430H) from the mother. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c. 978+ 1G>A was classified as a pathogenic variant (PVS1+ PM2_Supporting+ PP5), whilst the newly discovered c. 1288G>C (p.D430H) was classified as a likely pathogenic variant (PM2_Supporting+ PM3+ PM5+ PP3). Conclusion The c. 978+ 1G>A and c. 1288G>C (p.D430H) compound heterozygous variants of theTMEM67 gene probably underlay the three consecutive adverse pregnancies suspected for ciliopathy in this pedigree. The discovery of c. 1288G>C (p.D430H) has also expanded the mutational spectrum of theTMEM67 gene.

    纤毛病TMEM67基因高通量测序麦克尔综合征

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    F12基因复合杂合变异致遗传性FⅫ缺陷症一个家系的遗传学分析

    叶佳佳李永燕周静珍杨雅芸...
    1241-1245页
    查看更多>>摘要：目的 对1个遗传性凝血因子Ⅻ(FⅫ)缺陷症家系进行实验室表型和基因变异分析，初步探讨其分子发病机制。 方法 选取2021年7月17日因"慢性胃炎"就诊于宁波市第二医院的1例遗传性FⅫ缺陷症男性先证者及其家系成员(共3代7人)作为研究对象。检测先证者及其家系成员凝血酶原时间(PT)、活化部分凝血活酶时间(APTT)、凝血因子Ⅷ活性(FⅧ：C)、凝血因子Ⅸ活性(FⅨ：C)、凝血因子Ⅺ活性(FⅪ：C)、FⅫ活性(FⅫ：C)和FⅫ抗原(FⅫ：Ag)等指标以明确诊断。采用DNA直接测序分析F12基因的所有外显子、侧翼、5′和3′非翻译区及家系成员相应的变异位点区域，用克隆测序进一步证实所发生的变异。用生物信息学软件分析变异对蛋白功能的影响。 结果 先证者为47岁男性，APTT为180.0 s，明显延长，FⅫ：C和FⅫ：Ag均<1.0%，极度降低。先证者父亲、母亲、弟弟、大儿子及小儿子FⅫ：C和FⅫ：Ag均有不同程度降低。基因分析显示先证者F12基因第10外显子存在c.1092_1093insC(p.Lys365Glnfs*69)杂合插入变异及第14外显子存在c.1792_1796delGTCTA(p.Val579Hisfs*32)杂合缺失变异，c.1092_1093insC为已报道的致病性变异。其母亲和大儿子携带c.1092_1093insC杂合插入变异，父亲、弟弟和小儿子携带c.1792_1796delGTCTA杂合缺失变异。第1外显子启动子区46C/T多态性分析显示先证者、大儿子和小儿子为46T/T型，其余人均为46C/T型。生物信息学软件分析第579位氨基酸残基为高度保守的位点，变异后增加了一个苯环及周围氨基酸的氢键发生了改变。根据美国医学遗传学与基因组学学会相关遗传变异分类标准和指南，c.1792_1796delGTCTA变异评级为致病性变异(PVS1＋PM2_Supporting＋PM4)。 结论 F12基因母源的c.1092_1093insC(p.Lys365Glnfs*69)杂合插入变异及父源的c.1792_1796delGTCTA(p.Val579Hisfs*32)杂合缺失变异可能是该家系FⅫ水平降低的原因。上述发现丰富了FⅫ缺乏症的基因-表型谱。 Objective To explore the laboratory phenotype and molecular pathogenesis in a Chinese pedigree affected with Hereditary coagulation factor Ⅻ (FⅫ) deficiency. Methods A male proband admitted to Ningbo No.2 Hospital on July 17, 2021 due to chronic gastritis and members of his pedigree (7 individuals from three generations) were selected as the study subjects. Prothrombin time (PT), activated partial thromboplastin time (APTT), FⅧ activity (FⅧ: C), FⅨ activity (FⅨ: C), FⅪ activity (FⅪ: C), FⅫ activity (FⅫ: C), and FⅫ antigen (FⅫ: Ag) were determined. All of the exons, exon-intronic boundaries, as well as the 5′- and 3′-untranslated regions of the F12 gene were subjected to Sanger sequencing. Candidate variants were verified by cloning sequencing. The effect of candidate variants on the protein function was analyzed by bioinformatics software. Results The proband, a 47-year-old male, had significantly prolonged APTT (180.0 s) and decreased FⅫ: C and FⅫ: Ag levels (< 1%). His father, mother, brother and two sons also showed certain degrees of reduction. Genetic testing revealed that the proband has harbored compound heterozygous variants of theF12 gene, namely c. 1092_1093insC (p.Lys365Glnfs*69) in exon 10 and c. 1792_1796delGTCTA (p.Val579Hisfs*32) in exon 14. His mother and elder son were heterozygous for the c. 1092_1093ins variant, whilst his father, brother, and younger son were heterozygous for the c. 1792_1796delGTCTA variant. Analysis of the promoter region of exon 1 also showed that the proband and both sons had harbored a 46T/T polymorphism, whilst other family members were 46C/T. Bioinformatic analysis suggested that the p. Val579 is a highly conserved site. Protein model analysis showed that, with the p. Val579Hisfs*32 variant, a benzene ring was added and the hydrogen bond of surrounding amino acids was changed. Based on the guidelines from the American College of Medical Genetics and Genomics, the c. 1792_1796delGTCTA was classified as a pathogenic variant (PVS1+ PM2_Supporting+ PM4). Conclusion The c. 1092_1093insC (p.Lys365Glnfs*69) and c. 1792_1796delGTCTA (p.Val579Hisfs*32) compound heterozygous variants of the F12 gene probably underlay the decreased FⅫ levels in this pedigree. Above finding has also enriched the mutational spectrum for FⅫ deficiency.

    凝血因子ⅫF12基因基因变异家系

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    TNNI3与 TAZ基因变异所致罕见心脏病一个家系的研究

    徐惠玲胡锐江璇雷钏...
    1246-1251页
    查看更多>>摘要：目的 鉴定1例罕见心脏病家系(Barth综合征以及肥原性心肌病)的遗传学病因，为该家系提供遗传咨询及生育指导。 方法 选取2021年7月9日于南方医科大学附属深圳市妇幼保健院就诊的1个罕见心脏病家系作为研究对象。收集家系成员的临床资料，对患儿及其父母进行家系全外显子组测序(Trio-WES)，对家系其他成员进行Sanger测序验证，对变异进行生物学信息分析。参照美国医学遗传学与基因组学学会(ACMG)相关指南判断变异的致病性。 结果 Trio-WES检测显示先证者携带TAZ基因c.542G>A(p.G181A)半合子变异，该变异遗传自其母亲；此外，其母亲还携带TNNI3基因c.557G>A(p.R186Q)变异。经Sanger测序验证，先证者姨母与外祖母同样携带该变异。参照ACMG相关指南，TAZ基因c.542G>A(p.G181A)评定为可能致病性变异(PS2_Strong＋PM2_Supporting＋PP3)，TNNI3基因c.557G>A(p.R186Q)评定为致病性变异(PP1_Strong＋PS4_Strong＋PP3＋PP4＋PM2_Supporting)。 结论 TAZ基因c.542G>A(p.G181A)可能是先证者患Barth综合征的遗传学病因，TNNI3基因c.557G>A(p.R186Q)变异可能为先证者母亲、姨母及外祖母患肥厚型心肌病的遗传学病因。上述发现拓展了TAZ基因的变异谱，为该家系的临床诊断提供了参考。 Objective To explore the genetic basis for a Chinese pedigree affected with rare type heart disease. Methods A pedigree identified at Shenzhen Maternity and Child Health Care Hospital Affiliated to Southern Medical University on July 9, 2021 was selected as the study subject. Clinical data were collected. Trio-whole exome sequencing (WES) was carried out for the proband and his parents. Candidate variants were validated by Sanger sequencing of his family members and bioinformatic analysis. Results The proband, a 5-month-old male, was found to have Barth syndrome (dilated myocardiopathy and left ventricular non-compaction). Trio-WES revealed that he has harbored a hemizygous c. 542G>A (p.G181A) variant of theTAZ gene, which was inherited from his mother. In addition, his mother, aunt and maternal grandmother were also found to harbor a c. 557G>A (p.R186Q) variant of theTNNI3 gene. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c. 542G>A (p.G181A) variant of theTAZ gene was classified as likely pathogenic (PS2_Strong+ PM2_Supporting+ PP3), whilst the c. 557G>A (p.R186Q) variant of theTNNI3 gene was classified as pathogenic (PP1_Strong+ PS4_Strong+ PP3+ PP4+ PM2_Supporting). Conclusion The c. 542G>A (p.G181A) variant of the TAZ gene probably underlay the Barth syndrome in the proband, and the c. 557G>A (p.R186Q) variant of theTNNI3 gene may be responsible for the hypertrophic cardiomyopathy in his mother, aunt and maternal grandmother. Above finding has expanded the mutational spectrum of the TAZ gene and facilitated the diagnosis of this pedigree.

    TNNI3基因TAZ基因Barth综合征肥厚型心肌病

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