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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。
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    无创产前检测提示罕见常染色体三体胎儿的产前诊断与妊娠结局

    代鹏赵干业胡爽刘宁...
    513-518页
    查看更多>>摘要：目的 探讨无创产前检测(NIPT)提示的罕见常染色体三体(RATs)的产前诊断结果及妊娠结局。 方法 以2016年1月至2020年12月在郑州大学第一附属医院遗传与产前诊断中心接受NIPT检测的69 608例孕妇作为研究对象。回顾性分析RATs高风险孕妇的产前诊断结果及妊娠结局。 结果 在69 608例孕妇中，共有161例(0.23%)NIPT检测提示RATs高风险，其中最常见者为7三体(17.4%，28/161)与8三体(12.4%，20/161)，最罕见者为17三体(0.6%，1/161)。98例RATs高风险孕妇接受了侵入性产前诊断，12例胎儿被确诊存在染色体异常，5例与NIPT的结果一致，阳性预测值为5.26%(5/98)。在161例孕妇中，成功随访153例(95%)，在最终出生的139例胎儿中，仅1例存在表型异常。 结论 NIPT提示RATs高风险的孕妇多数具有良好的妊娠结局，建议其通过侵入性产前诊断或连续的超声检查监测胎儿的发育生长情况，而不是直接终止妊娠。 Objective To analyze the result of prenatal diagnosis and outcome of pregnancy for fetuses with rare autosomal trisomies (RATs) suggested by non-invasive prenatal testing (NIPT). Methods A total of 69 608 pregnant women who underwent NIPT at Genetics and Prenatal Diagnosis Center of the First Affiliated Hospital of Zhengzhou University from January 2016 to December 2020 were selected as study subjects. The result of prenatal diagnosis and outcome of pregnancy for those with a high risk for RATs were retrospectively analyzed. Results Among the 69 608 pregnant women, the positive rate of NIPT for high-risk RATs was 0.23% (161/69 608), with trisomy 7 (17.4%, 28/161) and trisomy 8 (12.4%, 20/161) being the most common, and trisomy 17 (0.6%, 1/161) being the rarest. For 98 women who had accepted invasive prenatal diagnosis, 12 fetal chromosomal abnormalities were confirmed, and in 5 cases the results were consistent with those of NIPT, which yielded a positive predictive value of 5.26%. Among the 161 women with a high risk for RATs, 153 (95%) were successfully followed up. 139 fetuses were ultimately born, with only one being clinically abnormal. Conclusion Most women with a high risk for RATs by NIPT have good pregnancy outcomes. Invasive prenatal diagnosis or serial ultrasonography to monitor fetal growth, instead of direct termination of pregnancy, is recommended.

    无创产前检测罕见常染色体三体产前诊断妊娠结局孕妇

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    基于多因素非条件Logistic回归分析探讨无创产前检测技术筛查失败的影响因素

    石杨姜海燕邵小光梁程红...
    519-526页
    查看更多>>摘要：目的 探讨无创产前检测(NIPT)技术筛查失败影响因素的多因素非条件Logistic回归分析。 方法 选取2019年7月至2020年6月就诊于大连市妇女儿童医疗中心的3 410例孕妇为研究对象。采取回顾性分析方法，按照首次NIPT筛查结果，将其分为首次成功组(n＝3 350)与首次失败组(n＝60)。采集2组孕妇年龄、体重、身体质量指数(BMI)、取样孕龄、妊娠类型(单胎/双胎)、是否经产、肝素治疗史、受孕方式[自然受孕/辅助生殖技术助孕(ART)]等临床资料。2组孕妇临床资料比较采用独立样本t检验和χ2检验，多因素非条件Logistic回归分析探讨影响NIPT筛查失败因素，运用ROC曲线分析评价诊断及预测效果。 结果 本研究共纳入3 410例孕妇，首次成功组3 350例，首次失败组60例，NIPT首次失败率为1.76%(60/3 410)。2组孕妇在年龄、体重、BMI和受孕方式(自然受孕/ART)差异无统计学意义(P>0.05)。与首次成功组相比，首次失败组的取样孕龄、经产妇比例较低，双胎妊娠和肝素治疗比例较高(P<0.05)。多因素非条件Logistic回归分析显示，取样孕龄(OR＝0.931，95%CI：0.845~1.026，P<0.001)和肝素使用史(OR＝8.771，95%CI：2.708~28.409，P<0.001)是孕妇首次NIPT失败的独立影响因素。取样孕龄单因素非条件Logistic回归分析显示，NIPT筛查失败的回归方程为Logit(P)＝-9.867+0.319×取样孕龄，ROC曲线下面积为0.742，约登指数为0.427，截断值为16.36周。 结论 取样孕龄和使用肝素治疗是NIPT首次筛查失败的独立影响因素。基于Logistic回归分析及ROC曲线评估取样孕龄对首次NIPT筛查失败的预测价值，建立回归方程，确定最佳取样孕龄为16.36周，可为NIPT筛查时机提供一定参考依据。 Objective To explore the factors for the failure of non-invasive prenatal testing (NIPT) through multifactorial unconditional Logistic regression analysis. Methods A total of 3 410 pregnant women who had visited Dalian Women and Children Medical Group from July 2019 to June 2020 were selected as the study subjects and divided into first success NIPT group (n = 3 350) and first failed group (n = 60). Clinical data including age, weight, body mass index (BMI), gestational week, type of pregnancy (singleton/twin), history of delivery, heparin treatment, and conception method [natural conception/assisted reproductive technology (ART)] were collected. Independent sample t-test and Chi-square test were carried out for comparing the two groups, and multi-factorial unconditional Logistic regression analysis was carried out to explore the factors for the failure of NIPT, and receiver operating characteristic curve (ROC) analysis was used to evaluate the diagnosis and predictive effects. Results Among the 3 410 pregnant women, 3 350 were assigned to the first success NIPT group, and 60 were assigned to the first failed group, and the first-time failure rate was 1.76% (60/3 410). No significant difference was found in age, weight, BMI and method of conception between the two groups (P > 0.05). Compared with first success group, first failed group had lower sampling gestational weeks, lower proportion of women with previous history of delivery, and higher proportion of twin pregnancies and heparin treatment ( P < 0.05). Multi-factorial unconditional Logistic regression analysis indicated that sampling gestational week ( OR = 0.931, 95%CI: 0.845 ~ 1.026, P < 0.001) and history of heparin use ( OR = 8.771, 95%CI: 2.708 ~ 28.409, P < 0.001) are independent factors for first failed NIPT. One-way unconditional Logistic regression analysis for sampling gestational weeks indicated that the regression equation for NIPT screening failure was Logit ( P) = -9.867 + 0.319 × sampling gestational week, with the area under the ROC curve being 0.742, a Jordan index of 0.427, and a cutoff value of 16.36 weeks. Conclusion Gestational week and heparin treatment are independent factors for the first failed NIPT. A regression equation has been established and determined the optimal sampling gestational week to be 16.36 weeks, which may provide a reference for the timing of NIPT screening.

    无创产前检测游离胎儿DNALogistic回归分析肝素孕龄

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    染色体微阵列分析和荧光原位杂交技术对于产前诊断染色体嵌合体的价值

    郑建丽安宁李敏许孟军...
    527-531页
    查看更多>>摘要：目的 探讨染色体微阵列分析(CMA)和荧光原位杂交(FISH)技术对于产前诊断染色体嵌合体的应用价值。 方法 选取2018年1月至2020年12月就诊于盐城市妇幼保健院产前诊断中心的775例孕妇作为研究对象。对其同时进行染色体核型分析和CMA检测，对部分疑似存在嵌合者进行FISH检测。 结果 在775份羊水标本中，核型分析共发现嵌合体13例，检出率为1.55%。性染色体数目异常嵌合、性染色体结构异常嵌合、常染色体数目异常嵌合和常染色体结构异常嵌合者分别为4例、3例、4例和2例。13例核型分析发现的嵌合体中，CMA检测仅发现了6例。3例经FISH验证的孕妇中，2例与核型及CMA结果一致，并且明确为低比例嵌合；1例与核型分析的结果一致，但CMA检测未见异常。8例嵌合体孕妇选择终止妊娠(性染色体嵌合5例，常染色体嵌合3例)。 结论 对于产前诊断疑似存在染色体嵌合的病例，应联合应用CMA、FISH与G显带核型技术准确判读嵌合类型和比例，为临床遗传咨询提供更为全面的信息。 Objective To assess the value of chromosomal microarray analysis (CMA) and fluorescence in situ hybridization (FISH) for the prenatal diagnosis of chromosomal mosaicisms. Methods A total of 775 pregnant women who had visited the Prenatal Diagnosis Center of Yancheng Maternal and Child Health Care Hospital from January 2018 to December 2020 were selected as study subjects. Chromosome karyotyping analysis and CMA were carried out for all women, and FISH was used to validate the suspected mosaicism cases. Results Among the 775 amniotic fluid samples, karyotyping has identified 13 mosaicism cases, which yielded a detection rate of 1.55%. Respectively, there were 4, 3, 4 and 2 cases for sex chromosome number mosaicisms, abnormal sex chromosome structure mosaicisms, abnormal autosomal number mosaicisms and abnormal autosomal structure mosaicisms. CMA has only detected only 6 of the 13 cases. Among 3 cases verified by FISH, 2 cases were consistent with the karyotyping and CMA results, and clearly showed low proportion mosaicism, and 1 case was consistent with the result of karyotyping but with a normal result by CMA. Eight pregnant women had chosen to terminate the pregnancy (5 with sex chromosome mosaicisms and 3 with autosomal mosaicisms). Conclusion For fetuses suspected for chromosomal mosaicisms, CMA, FISH and G-banding karyotyping should be combined to determine the type and proportion of mosaicisms more precisely in order to provide more information for genetic counseling.

    核型分析染色体微阵列分析荧光原位杂交嵌合体产前诊断

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    不同检测技术对颈项透明层增厚胎儿的产前诊断结果的比较

    代文成刘新红马晓蓉余珍...
    532-537页
    查看更多>>摘要：目的 探讨染色体微阵列分析(CMA)和家系全外显子组测序(trio-WES)对于颈项透明层(NT)增厚胎儿的诊断价值。 方法 选择2018年6月至2020年6月因妊娠11~13+6周超声筛查提示胎儿NT≥3.0 mm在乌鲁木齐市妇幼保健院就诊的62例孕妇作为研究对象，将其分为NT 3.0 ~ <3.5 mm组( n＝33)和≥3.5 mm组(n＝29)。抽取孕妇的羊水样本，进行染色体核型分析及CMA检测，并对15例CMA检测未见异常的样本进行trio-WES分析。用χ2检验比较2组染色体异常的分布与NT厚度的相关性。 结果 62例产妇的中位年龄为29岁(22~41岁)，胎儿NT的中位厚度为3.4 mm(3.0~9.1 mm)，发现NT异常时的中位胎龄为13+4周(11+5~13+6周)。染色体核型分析共检出12例非整倍体，1例衍生染色体，检出率为20.97%(13/62)。CMA共检出12例非整倍体、1例致病性拷贝数变异(CNV)和5例临床意义不明CNV，检出率为29.03%(18/62)。≥3.5 mm组胎儿的非整倍体检出率高于3.0~<3.5 mm组[3.03%(1/33)vs. 41.38%(12/29)，χ2 ＝ 13.698，P<0.001]。2组胎儿致病和临床意义不明CNV检出率差异无统计学意义(χ2 ＝ 0.028，P>0.05)。对15例CMA未见异常且不伴结构畸形的家系进行trio-WES分析，共发现6种基因变异，包括SOS1: c．3542C>T(p.A1181V)和c.3817C>G(p.L1273V)杂合变异，COL2A1: c．436C>T(p.P146S)和c.3700G>A(p.D1234N)杂合变异，LZTR1: c．1496T>C(p.V499A)和BRAF: c．64G>A(p.D22N)杂合变异。根据美国医学遗传学与基因组学学会相关指南，均评级为临床意义不明。 结论 NT增厚可在一定程度上提示胎儿染色体异常，可利用CMA与trio-WES技术对其进行产前诊断。 Objective To assess the value of chromosomal microarray analysis (CMA) and trio-whole exome sequencing (trio-WES) for fetuses with increased nuchal translucency (NT) thickness. Methods sixty two pregnant women who had visited Urumqi Maternal and Child Care Health Hospital between June 2018 and June 2020 for NT≥3.0 mm at 11~13+ 6 gestational weeks were selected as study subjects. Relevant clinical data were collected. The patients were divided into 3.0~<3.5 mm (n=33) and ≥3.5 mm groups (n=29). Chromosome karyotyping analysis and chromosomal microarray analysis were carried out. And trio-WES analysis was performed on 15 samples with NT thickening but negative CMA results. The distribution and incidence of chromosomal abnormalities in the two groups were compared by using chi-square test. Results The median age of the pregnant women was 29 years old (22~41 years old), the median thickness of NT was 3.4 mm (3.0~9.1 mm), and the median gestational age at the detection was 13+ 4 weeks (11+ 5~13+ 6 weeks). Chromosome karyotyping analysis has detected 12 cases of aneuploidies and 1 case of derivative chromosome. The detection rate was 20.97% (13/62). CMA has detected 12 cases of aneuploidies, 1 case of pathogenic CNV and 5 cases of variant of uncertain significance (VUS), with a detection rate of 29.03% (18/62). The aneuploidy rate for the NT≥3.5 mm group was higher than that for the 3.0≤NT<3.5 mm group [3.03% (1/33)vs. 41.38% (12/29), χ2 = 13.698, P<0.001]. There was no statistically significant difference between the two groups in the detection rate of fetal pathogenic CNV and VUS(χ2 = 0.028, P>0.05). Trio-WES analysis of 15 samples with negative CMA result and no structural abnormality has identified 6 heterozygous variants, includingSOS1: c. 3542C>T (p.A1181V) and c. 3817C>G (p.L1273V),COL2A1: c. 436C>T (p.P146S) and c. 3700G>A (p.D1234N),LZTR1: c. 1496T>C (p.V499A), andBRAF: c. 64G>A (p.D22N), respectively. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), all of the variants were rated as VUS. Conclusion NT thickening can indicate chromosome abnormality, and CMA and trio-WES may be used for the prenatal diagnosis.

    产前诊断颈项透明层全外显子组测序染色体微阵列分析胎儿孕妇

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    单绒毛膜双胎遗传物质不一致的临床分析

    汤璐潘平山孙惟佳覃洁...
    538-542页
    查看更多>>摘要：目的 探讨5例遗传物质不一致的单绒毛膜双羊膜囊(MCDA)双胎的遗传学病因。 方法 选取2016年1月至2020年6月于广西壮族自治区妇幼保健院产科进行双胎羊膜腔穿刺产前诊断的148例MCDA双胎为研究对象。收集孕妇的临床资料，分别采集双胎的羊水样本进行染色体核型分析及单核苷酸多态性微阵列(SNP array)检测。 结果 染色体核型分析显示，148例MCDA双胎中有5例染色体核型不一致，发生率为3.4%(5/148)。SNP array检测显示其中3例胎儿为嵌合体。 结论 MCDA双胎存在遗传物质不一致的现象，其产前诊断需具有丰富经验的医学遗传学和胎儿医学专家共同完成，临床处理应该遵循个体化原则。 Objective To explore the genetic etiology of 5 cases of monochorionic-diamniotic (MCDA) with genetic discordance. Methods 148 cases of MCDA twins who were diagnosed by amniocentesis at the Maternal and Child Health Care Hospital of Guangxi Zhuang Autonomous Region from January 2016 to June 2020 were selected as the study subjects. Relevant clinical data of the pregnant women were collected, and amniotic fluid samples of the twins were collected separately. Chromosomal karyotyping analysis and single nucleotide polymorphism array (SNP array) assay were carried out. Results The results of chromosomal karyotyping analysis showed that 5 of the MCDA twins had inconsistent chromosome karyotypes, with an incidence of 3.4% (5/148). SNP array assay showed that 3 fetuses were mosaics. Conclusion Genetic discordance occurs among MCDA twins, and prenatal counseling for such cases should be given by doctors with experience in medical genetics and fetal medicine, and personalized clinical management should be recommended.

    单绒毛膜双羊膜囊双胎不一致

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    复杂平衡易位1例

    谢良玉秦利赖怡许芯...
    542页
    查看更多>>摘要：男，47岁，汉族，2022年8月因"原发不育"就诊于四川大学华西第二医院。院外精液检查提示无精，前妻已结婚生子，现任妻子曾与前夫生育1子，外观无明显异常。夫妻系非近亲结婚，否认家族遗传病史。患者为初中文化，智力正常，长期久坐，身高为170 cm，体质量为74 kg，身体质量指数为25.61 kg/cm2。外生殖器发育PH4G4，左侧睾丸约为12 mL，右侧睾丸约为10 mL，均质地中等，未扪及明显异常。患者父母系非近亲结婚，拒绝做染色体核型分析。妹妹外观无异常，已结婚生子，无不良孕产史。染色体G显带分析示患者核型为46，XY，t(1；18)(q31；q12.2)，t(10；21；14)(q21.2；q21；p13)(图1)。染色体高通量测序分析未检测到有临床意义的缺失及重复。本研究通过了四川大学华西第二医院伦理委员会的审查(2019-077)，患者签署了临床研究知情同意书。
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    CTCF基因变异所致精神发育迟滞21型2例患儿的临床特征及遗传学分析

    律玉强宋风玲张开慧高敏...
    543-546页
    查看更多>>摘要：目的 分析2例发育迟缓患儿的临床及遗传学特征。 方法 以2021年8月18日就诊于山东大学附属儿童医院的2例患儿为研究对象，对其进行临床和实验室检查。采集患儿及其父母的外周血样，同时进行染色体核型和高通量测序分析。 结果 2例患儿均表现为不同程度的发育迟缓，染色体核型均为46，XX。高通量测序结果显示其分别携带CTCF基因c.489delG(p.Q165Rfs*14)和c.1157_1158delAT(p.Y386Cfs*22)移码变异，二者均为新发变异且既往未见报道。 结论 CTCF基因变异可能是2例患儿的遗传学病因。上述发现丰富了精神发育迟滞21型的基因变异谱，可为阐明该病基因型与表型的相关性提供线索。 Objective To explore the clinical and genetic characteristics of two children with developmental delay. Methods Two children who had presented at the Children′s Hospital Affiliated to Shandong University on August 18, 2021 were enrolled as the study subjects. Clinical and laboratory examination, chromosomal karyotyping and high-throughput sequencing were carried out for both children. Results Both children had a 46, XX karyotype. High-throughput sequencing showed that they have respectively carried a c. 489delG (p.Q165Rfs*14) and a c. 1157_1158delAT (p.Y386Cfs*22) frameshifting variant of the CTCF gene, both had a de novo origin and were unreported previously. Conclusion The CTCF gene variants probably underlay the development delay in the two children. Above discovery has enriched the mutational spectrum of the CTCF gene, and has important implications for revealing the genotype-phenotype correlation for similar patients.

    发育迟缓精神发育迟滞21型CTCF基因高通量测序

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    F12基因起始密码子c.1A>G变异所致遗传性凝血因子Ⅻ缺陷症一家系的遗传学分析

    季伟丹林森陈杰金超俊...
    547-551页
    查看更多>>摘要：目的 探讨1个姨表近亲婚配的遗传性凝血因子Ⅻ(FⅫ)缺陷症家系的临床特征与遗传学病因。 方法 选取2021年7月12日于瑞安市人民医院泌尿外科就诊的1个遗传性FⅫ缺陷症家系为研究对象。收集家系临床资料，抽取受试者外周静脉血样，分别进行凝血指标检测与基因检测，采用Sanger测序进行家系验证，并对候选变异进行生物信息学分析。 结果 遗传性FⅫ缺陷症家系成员共3代6人，包括先证者及其父亲、母亲、妻子、妹妹和儿子。先证者为男性，51岁，临床表现为肾结石。凝血指标检测结果显示，先证者活化部分凝血活酶时间(APTT)显著延长，FⅫ活性(FⅫ：C)与FⅫ抗原(FⅫ：Ag)均极度降低；先证者父亲、母亲、妹妹和儿子FⅫ：C和FⅫ：Ag均降低至正常参考值下限的一半左右。基因检测结果提示，先证者F12基因第1外显子起始密码子存在c.1A>G(p.Arg2Tyr)纯合错义变异。经Sanger测序验证，先证者父亲、母亲、妹妹和儿子均携带F12基因c.1A>G杂合变异，先证者妻子未见该变异。该变异在HGMD数据库未见报道。经SIFT在线软件分析，预测该变异为有害性变异；经Swiss-Pbd Viewerv4.0.1软件模拟，该变异对FⅫ蛋白的结构影响较大。根据美国医学遗传学与基因组学学会(ACMG)制订的《序列变异解释的标准和指南》，对该变异评级为可能致病性变异。 结论 F12基因c.1A>G(p.Arg2Tyr)变异可能为该姨表近亲婚配的遗传性FⅫ缺陷症家系的遗传学病因，进一步丰富了F12基因变异谱，为该病家系临床诊断与遗传咨询提供参考依据。 Objective To explore the clinical characteristics and genetic etiology of a consanguineous Chinese pedigree affected with Congenital coagulation factor Ⅻ (FⅫ) deficiency. Methods Members of the pedigree who had visited Ruian People′s Hospital on July 12, 2021 were selected as the study subjects. Clinical data of the pedigree were reviewed. Peripheral venous blood samples were taken from the subjects. Blood coagulation index and genetic testing were carried out. Candidate variant was verified by Sanger sequencing and bioinformatic analysis. Results This pedigree has comprised 6 individuals from 3 generations, including the proband, his father, mother, wife, sister and son. The proband was a 51-year-old male with kidney stones. Blood coagulation test showed that his activated partial thromboplastin time (APTT) was significantly prolonged, whilst the FⅫ activity (FⅫ: C) and FⅫ antigen (FⅫ: Ag) were extremely reduced. The FⅫ: C and FⅫ: Ag of proband′s father, mother, sister and son have all reduced to about half of the lower limit of reference range. Genetic testing revealed that the proband has harbored homozygous missense variant of c. 1A>G (p.Arg2Tyr) of the start codon in exon 1 of theF12 gene. Sanger sequencing confirmed that his father, mother, sister and son were all heterozygous for the variant, whilst his wife was of the wild type. By bioinformatic analysis, the variant has not been included in the HGMD database. Prediction with SIFT online software suggested the variant is harmful. Simulation with Swiss-Pbd Viewer v4.0.1 software suggested that the variant has a great impact on the structure of FⅫ protein. Based on the Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics (ACMG), the variant was rated as likely pathogenic. Conclusion The c. 1A>G (p.Arg2Tyr) variant of theF12 gene probably underlay the congenital FⅫ deficiency in this pedigree. Above finding has further expanded the spectrum of F12 gene variants and provided a reference for clinical diagnosis and genetic counseling for this pedigree.

    凝血因子ⅫF12基因近亲婚配

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    癫痫伴全面性发育迟缓患儿1例的临床特征及 PAK1基因变异分析

    袁梦张佳李杨罗欢...
    552-557页
    查看更多>>摘要：目的 探讨1例癫痫伴全面性发育迟缓患儿的临床特征与遗传学病因。 方法 选取2021年4月1日于四川大学华西第二医院小儿神经科就诊的1例癫痫伴全面性发育迟缓患儿为研究对象。收集患儿临床资料，抽取患儿及其父母外周静脉血样，应用全外显子组测序(WES)对患儿进行基因检测，采用Sanger测序进行家系验证，并对候选变异进行生物信息学分析。设定检索年限为2000年1月1日至2021年5月31日，在万方数据知识服务平台、中国知网、PubMed、ClinVar、Embase等数据库中，检索PAK1基因变异相关性癫痫病例报道，对该病患儿临床表型及PAK1基因变异情况进行总结。 结果 患儿为男性，2岁2个月，临床表现为癫痫、全面运动发育迟缓与大头畸形。WES检测结果提示，患儿携带PAK1基因c.1427T>C变异。经Sanger测序验证，患儿父母PAK1基因均为野生型，提示患儿为新发变异。生物信息学分析：PAK1基因c.1427T>C变异在dbSNP、OMIM、HGMD及ClinVar等数据库中，仅见1篇文献报道。在ExAC、1000 Genomes及gnomAD等数据库中，亚洲正常人群该变异未见携带频率。IFT、PolyPhen-2、LRT、Mutation Taster及FATHMM等在线软件预测结果均提示该变异对编码蛋白功能影响可能有害。根据美国医学遗传学与基因组学学会(ACMG)制订的《序列变异解释的标准和指南》，该变异评级为可能致病性变异。 结论 PAK1基因c.1427T>C变异可能为该癫痫伴全面性发育迟缓患儿的遗传学病因。本研究为该病患儿临床诊断与遗传咨询提供了参考依据。 Objective To investigate the clinical phenotype and genetic basis of a child with epilepsy and global developmental delay. Methods A child with epilepsy and global developmental delay who had visited West China Second University Hospital, Sichuan University on April 1, 2021 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 his parents. Whole exome sequencing (WES) was carried out for the child, and candidate variant was verified by Sanger sequencing and bioinformatic analysis. A literature review was also carried out by searching databases such as Wanfang data knowledge service platform, China National Knowledge Infrastructure, PubMed, ClinVar and Embase to summarize the clinical phenotypes and genotypes of the affected children. Results The child was a 2-year-and-2-month-old male with epilepsy, global developmental delay and macrocephaly. Results of WES showed that the child has harbored a c. 1427T>C variant of thePAK1 gene. Sanger sequencing confirmed that neither of his parents has carried the same variant. Only one similar case had been recorded by the dbSNP, OMIM, HGMD, and ClinVar databases. No frequency for this variant among Asian population was available in the ExAC, 1000 Genomes, and gnomAD databases. Prediction with IFT, PolyPhen-2, LRT, Mutation Taster, and FATHMM online software suggested that this variant is deleterious to the function of encoded protein. Based on the Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics (ACMG), the PAK1 gene c. 1427T>C variant was determined to be likely pathogenic. Conclusion The PAK1 gene c. 1427T>C variant probably underlay the epilepsy and global developmental delay in this child, which has provided a reference for the clinical diagnosis and genetic counseling in children with similar disorders.

    癫痫全面性发育迟缓大头畸形PAK1基因全外显子组测序儿童

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    产前诊断7号染色体短臂部分缺失1例

    张晨晖董叶林梦梦汪海...
    557页
    查看更多>>摘要：28岁，G3P1，孕12+5周超声测量胎儿颈后透明带为3.0 mm，孕中期血清学筛查21三体、18三体均为低风险，升级版无创产前检测提示胎儿7号染色体部分单体综合征高风险。夫妻双方外观无异常，否认孕早期毒物及放射物接触史。在签署知情同意书后，于孕18+4周抽取羊水30 mL以及双方外周血样各2 mL，其中10 mL羊水用于染色体微阵列分析(chromosomal microarray analysis，CMA)，结果为arr[hg19] 7p14.1p11.2(38529602_55367509)×1(图1)，提示胎儿7p14.1p11.2区存在约16.8 Mb的缺失。对剩余20 mL羊水进行常规细胞培养、制片、染色体G显带核型分析，参照《人类细胞遗传学国际命名体制(ISCN 2016)》进行描述，胎儿染色体核型为46，XN，del(7)(p11.2p14)(图2)。孕23+1周超声提示胼胝体发育不良可能、心脏发育异常(右心室双出口伴肺动脉狭窄可能、房室间隔缺损可能)。孕妇夫妇系非近亲结婚，否认家族遗传病史，第1胎生长发育未见明显异常，双方染色体核型未见明显异常，但拒绝接受CMA亲代验证。鉴于胎儿7号染色体短臂存在大片段缺失以及超声提示的结构异常，孕妇夫妇选择终止妊娠。本研究通过了温州市人民医院伦理委员会的审查[伦审(2021)第(56)改号]。
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