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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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    甘肃地区四氢生物蝶呤缺乏症18例患者的遗传学分析

    张钏田芯瑗王玉佩马盼盼...
    129-133页
    查看更多>>摘要：目的 探讨甘肃地区18例四氢生物蝶呤缺乏症(BH4D)患者的遗传学特征。 方法 选择2018年1月至2021年12月由甘肃省妇幼保健院医学遗传中心确诊的18例甘肃籍BH4D患者作为研究对象，对其进行全外显子组测序分析，并对候选变异进行Sanger测序家系验证。 结果 18例BH4D患者的36个等位基因均被成功检出，检出率为100.0%。其中16例是由PTS基因变异所致，2例是由QDPR基因变异所致。PTS基因共检测出10种不同的变异，其中热点变异为c.259C>T(34.38%)及c.286G>A(15.63%)。c.259C>T为已报道致病性变异，c.286G>A、c.166G>A、c.200C>T、c.272A>G、c.402A>C、c.421G>T、c.84-291A>G、c.317C>T为已报道的可能致病性变异。c.289_290insCTT既往未见报道，根据美国医学遗传学与基因组学学会变异相关指南评级为可能致病性变异(PM1＋PM2_Supporting＋PM3＋PP3＋PP4)。QDPR基因的c.478C>T和c.665C>T均被评级为临床意义未明变异(PM1＋PM2_Supporting＋PP3＋PP4)。 结论 基因检测明确了上述研究BH4D家系的基因变异情况，为及时准确的临床干预和患者家庭的遗传咨询和生育决策提供了依据。 Objective To explore the genetic basis of eighteen patients with tetrahydrobiopterin deficiency (BH4D) from Gansu Province. Methods Eighteen patients diagnosed with BH4D at Gansu Provincial Maternal and Child Health Care Hospital from January 2018 to December 2021 were selected as the study subjects. Whole exome sequencing was carried out, and candidate variants were verified by Sanger sequencing. Results All of the thirty-six alleles of the eighteen patients were successfully determined by molecular genetic testing. Sixteen patients were found to harbor variants of the PTS gene, and two had harbored variants of the QDPR gene. Ten variants were detected in the PTS gene, with the most common ones being c. 259C>T (34.38%) and c. 286G>A (15.63%). Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c. 259C>T was classified as a pathogenic variant, whilst the c. 286G>A, c. 166G>A, c. 200C>T, c. 272A>G, c. 402A>C, c. 421G>T, c. 84-291A>G and c. 317C>T were classified as likely pathogenic variants. A novel c. 289_290insCTT variant was classified as likely pathogenic (PM1+ PM2_Supporting+ PM3+ PP3+ PP4). The two variants (c.478C>T and c. 665C>T) detected in theQDPR gene were both classified as variants of uncertain significance (PM1+ PM2_Supporting+ PP3+ PP4). Conclusion Genetic testing has clarified the pathogenic variants in these BH4D patients, which has enabled timely and accurate clinical intervention and treatment, and provided a reference for genetic counseling and reproductive guidance for their families.

    四氢生物蝶呤缺乏症遗传学分析干预治疗遗传咨询家系

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    全外显子组测序在有免疫缺陷患儿夭折史夫妻双方隐性遗传病携带情况推断分析中的应用

    张冰杨科张玉薇娄桂予...
    134-139页
    查看更多>>摘要：目的 探讨全外显子测序技术在具有原发性免疫缺陷(PID)患儿夭折史但无先证者的夫妻双方隐性遗传病携带推断分析中的应用。 方法 收集2017年2月至2021年12月就诊于河南省人民医院因有疑似PID患儿生育史进行遗传学检查的4对夫妻的临床资料。对夫妻双方外周血样进行全外显子测序(WES)，就候选变异用Sanger测序或荧光定量PCR进行验证，并进一步对家系中的胎儿进行产前诊断。 结果 WES共检出6个与病史相关的致病或疑似致病的基因变异，包含有IL2RG、BTK、CYBB、DUOX2等基因，变异类型包括点变异、小片段缺失及外显子缺失等。其中DUOX2基因c.1265G>A、c.3329G>A，IL2RG基因c.676C>T为已报道致病性变异。IL2RG基因Exon5_8del、BTK基因c.184_185delAC、CYBB基因c.472A>T既往未见报道。根据美国医学遗传学与基因组学学会变异评级指南，IL2RG基因Exon5_8del、BTK基因c.184_185delAC、CYBB基因c.472A>T评级均为可能致病性变异(PVS1＋PM2_Supporting＋PP4)。其中3对夫妻再次妊娠后进行了产前诊断，结果显示胎儿BTK基因c.184_185、CYBB基因c.472、IL2RG基因c.676位点均为野生型，胎儿出生1年后随访未发现异常。 结论 全外显子组测序是具有免疫缺陷患儿夭折史夫妻双方隐性遗传病携带情况推断分析的一种重要手段，可提高阳性检出率。 Objective To explore the value of whole exome sequencing for the inferential analysis of recessive genetic disease carrier status for couples with a child died of Primary immunodeficiency (PID). Methods Clinical data was collected from four couples with a childbearing history of PID who had sought genetic counseling and undergone genetic testing at Henan Provincial People′s Hospital from February 2017 to December 2021. Whole exome sequencing (WES) was performed on both partners of each couple, and candidate variants were validated by Sanger sequencing and fluorescent quantitative PCR. Prenatal diagnosis was conducted on fetuses of these couples after confirming the variants. Results A total of six variants were detected in four genes including IL2RG, BTK, CYBB, and DUOX2. Among these, the c.1265G>A and c.3329G>A variants of theDUOX2 gene and the c. 676C>T variant of theIL2RG gene were previously known as pathogenic variants. On the other hand, the Exon5_8del variant of the IL2RG gene, the c. 184_185delAC variant of the BTK gene, and the c. 472A>T variant of theCYBB gene were unreported previously. Based on the guidelines from the American College of Medical Genetics and Genomics, the IL2RG: Exon5_8del, BTK: c. 184_185delAC and CYBB: c. 472A>T variants were classified as likely pathogenic (PVS1+ PM2_Supporting+ PP4).Prenatal diagnosis was conducted for three couples during their subsequent pregnancies, and the results revealed that the fetuses had the wild-type genotypes at the c. 184_185 position of theBTK gene, the c. 472 position of the CYBB gene, and the c. 676 position of the IL2RG gene. Follow-up examinations one year after birth has found no abnormality in the infants. Conclusion WES is an important tool to infer and analyze the carryier status for couples who had given births to children died of PID and improve the positive detection rate.

    免疫缺陷全外显子组测序基因变异隐性遗传病

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    7q11.23重复综合征10个家系的临床与遗传学分析

    时盼来刘永超侯雅勤陈铎...
    140-144页
    查看更多>>摘要：目的 分析10个7q11.23重复综合征家系的临床与遗传学特点。 方法 以2017年12月至2022年1月就诊于郑州大学第一附属医院遗传与产前诊断中心的10个7q11.23重复综合征家系作为研究对象，对病例进行低深度全基因组测序或单核苷酸多态性芯片检测，分析其临床表型和遗传方式。 结果 10个家系中包括6个产前病例与4个青少年病例。在6个产前病例中，有4例超声显示异常，包括3例软指标异常与1例胎儿结构发育异常。4个青少年病例的临床表型包括智力低下、语言发育落后以及注意缺陷多动障碍等。12个病例的7q11.23重复范围为1.31 ～ 1.42 Mb，涉及7q11.23重复综合征的经典区域；其中5例进行了家系验证，3例为新发变异，2例遗传自亲代。 结论 7q11.23重复综合征临床表型可能有明显异质性，应重视孕前咨询和医学指导。 Objective To analyze the clinical and genetic characteristics of ten Chinese pedigrees affected with 7q11.23 duplication syndrome. Methods From December 2017 to January 2022, ten pedigrees diagnosed with 7q11.23 duplication syndrome at the First Affiliated Hospital of Zhengzhou University were enrolled as the study subjects. Clinical data of all subjects were collected, and some had subjected to copy number variation sequencing or single nucleotide polymorphism array to analyze the pattern of inheritance. Results The probands had included six fetuses and four adolescents. Four of the six prenatal cases showed abnormal ultrasound indicators, including three with soft indicators and one with abnomal feta structural development. The clinical phenotype of the four adolescent cases had included mental retardation, delayed language development, and attention deficit hyperactivity disorder. The size of the copy number variations had ranged from 1.31 to 1.42 Mb, involving the classic region of 7q11.23 duplication syndrome. Of these, five cases had undergone parental origin testing, three cases were de novo, and two were hereditary. Conclusion Individuals with 7q11.23 duplication syndrome may show substantial clinical phenotypic heterogeneity, hence the affected families should be provided with pre-pregnancy consultation and reproductive guidance.

    7q11.23重复综合征家系分析表型异质性智力低下

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    中央型22q11.2缺失综合征8例的遗传学诊断与分析

    郭静李鹏云车佳翟闪闪...
    145-149页
    查看更多>>摘要：目的 探讨LCR22B/C～D型的中央型22q11.2缺失综合征胎儿的妊娠结局及产后临床表型。 方法 收集2019年1月至2022年4月于郑州大学第三附属医院产前诊断中心通过染色体微阵列分析(CMA)技术确诊为中央型22q11.2缺失的病例，分析胎儿产前影像学表现、父母CMA验证结果、妊娠结局及产后临床表型。 结果 共纳入8例中央型22q11.2缺失病例，其中6例为LCR22B～D型22q11.2缺失，2例为LCR22C～D型22q11.2缺失。6例LCR22B～D型22q11.2缺失中有3例超声提示心血管系统异常(胎儿右位主动脉弓、室间隔缺损、三尖瓣轻度反流)，1例提示泌尿系统异常(胎儿右肾异位)；2例LCR22C～D型22q11.2缺失超声提示羊水过少合并生长受限、胎儿颈后皮肤层增厚，均为非特异性影像学表现。6例进行了父母CMA亲本验证，均遗传自父母，其中5例继续妊娠至足月，产后随访患儿体格与智力发育均未见异常，1例因胎儿右肾异位选择终止妊娠；2例未进行父母CMA验证，选择了终止妊娠。 结论 上述研究的LCR22B/C～D型的中央型22q11.2缺失综合征不同于经典的22q11.2缺失综合征，其遗传信息主要来源于父母，产前影像学主要表现为心血管和泌尿系统异常，出生后体格及智力发育均未见异常，应为父母提供客观的产前遗传咨询。 Objective To explore the pregnancy outcome and postpartum clinical phenotype of LCR22B/C~D central 22q11.2 deletion syndrome. Methods For fetuses diagnosed with central 22q11.2 deletion by chromosomal microarray analysis (CMA) at the Prenatal Diagnosis Center of the Third Affiliated Hospital of Zhengzhou University from January 2019 to April 2022, their prenatal imaging, parental CMA verification, pregnancy outcomes and postpartum clinical phenotype were analyzed. Results Eight cases of central 22q11.2 deletion syndrome were included, including six cases with LCR22B~D 22q11.2 deletions and two with LCR22C~D 22q11.2 deletions. Among the six cases with LCR22B~D type 22q11.2 deletions, three had shown cardiovascular malformations (right aortic arch, ventricular septal defect, mild tricuspid regurgitation), one had shown urinary defect (right kidney heterotopia). Two cases with LCR22C~D 22q11.2 deletions showed nonspecific ultrasonographic findings, including oligohydramnios with growth restriction and nuchal skin thickening. The CMA verification showed that six cases were inherited from their parents, and five couples had chosen to continue with the pregnancy. Postpartum follow-up showed that the physical and intellectual development of all children were normal. One couple had opted to terminate the pregnancy considering the ectopic fetal right kidney. Two remaining cases had decided to terminate their pregnancies without parental verification. Conclusion The central 22q11.2 deletion syndrome of the LCR22B/C~D type is different from the classical types. Its genetic information mainly comes from parents. Prenatal imaging has mainly shown cardiovascular and urinary abnormalities. Postnatal growth and intellectual development have been normal. Therefore, the couples should be provided with suffice prenatal genetic counseling.

    中央型22q11.2缺失综合征产前表型遗传咨询

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    肾透明细胞癌患者肾组织干扰素调节因子6基因启动子区甲基化与总生存率的相关性研究

    张洁心陈灿卫宇昂陈林媛...
    150-156页
    查看更多>>摘要：目的 探讨干扰素调节因子6(IRF6)基因启动子甲基化在判断肾透明细胞癌(KIRC)患者预后中的价值。 方法 收集2016年1月至2020年1月在南京医科大学第一附属医院首诊的50例KIRC患者的原发灶组织，采用免疫组化法检测其IRF6蛋白的表达情况，并分析IRF6表达水平与患者生存及肿瘤转移的关系。使用生物信息学方法分别比较KIRC和正常肾组织中IRF6的mRNA及蛋白水平差异，基于大数据库分析癌和癌旁组织中IRF6基因启动子区甲基化率差异；将IRF6基因启动子区甲基化状态与患者总生存率(OS)进行统计分析，筛选出呈现显著负相关的区域，利用细胞系体外验证该启动子区甲基化区域与IRF6转录水平的关系。 结果 KIRC组织中IRF6 mRNA和蛋白水平均显著低于正常样本(P<0.05)，该现象在死亡或发生肿瘤转移的KIRC患者中较为突出。KIRC组织中IRF6基因启动子区甲基化程度远高于临近正常肾组织，并且IRF6基因启动子区甲基化与IRF6 mRNA之间存在显著负相关性(R＝-0.52)。IRF6基因启动子区域cg12034118和cg16030177的甲基化程度越高，患者OS越短且预后越差；体外KIRC细胞系实验证实，仅cg12034118中有20个CpG位点呈高度甲基化，使用去甲基化试剂5-Aza-CdR处理KIRC细胞系后IRF6转录水平可呈时间和剂量依赖显著性上调(P<0.05)。 结论 KIRC患者肾组织中IRF6基因启动子区甲基化与OS密切相关。cg12034118提示可作为供实验室检测的生物标志物，其高甲基化率对KIRC患者的预后判断有一定参考价值。 Objective To assess the prognostic value of methylation of interferon regulatory factor 6 (IRF6) gene promoter in patients diagnosed with Kidney renal clear cell carcinoma (KIRC). Methods The primary lesions of fifty KIRC patients who were diagnosed at the First Affiliated Hospital of Nanjing Medical University from January 2016 to January 2020 were collected. The expression of IRF6 protein was determined with an immunohistochemical method. The correlation between the level of IRF6 expression and survival and/or metastasis status was analyzed. The mRNA and protein levels of the IRF6 in KIRC and normal renal tissues were compared by using bioinformatic tools. The difference in the methylation rate of the IRF6 gene promoter between tumor and adjacent tissues was analyzed by searching the online databases. Statistical analysis was carried out for the methylation status of the IRF6 gene promoter region to select those negatively correlated with the overall survival (OS) among the patients. In vitro experiments were conducted with cell lines to verify the correlation between the status of promoter methylation and transcription level of the IRF6 gene. Results The mRNA and protein levels of the IRF6 gene in KIRC tissues were significantly lower than those of the normal controls, and this was more prominent in patients who had died or developed metastasis. The extent of IRF6 gene promoter methylation in the KIRC tissues was much higher compared with that of the adjacent normal renal tissues. There was a significant negative correlation between the methylation of the IRF6 gene promoter and mRNA level of the IRF6 (R= -0.52). The higher methylation degree in the IRF6 gene promoter regions cg12034118 and cg16030177, the shorter the OS and worse prognosis in the patients. Only twenty CpG sites in cg12034118 were confirmed to be highly methylated in KIRC cell lines. The transcription level of the IRF6 gene was upregulated in a time- and dose-dependent manner after the treatment with demethylation reagent 5-azadeoxycytidine. Conclusion The methylation of IRF6 gene promoter in the renal tissues of KIRC patients is closely correlated with the OS. Cg12034118 may provide a promising biomarker for laboratory detection, and its high methylation rate has certain reference value for the prognosis.

    干扰素调节因子6肾透明细胞癌甲基化总生存率

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    整联蛋白α4和细胞间黏附分子1基因多态性与克罗恩病发病风险及其临床病理特征的相关性

    张顶力吴昊邵晓晓肖慧盈...
    157-166页
    查看更多>>摘要：目的 探讨整联蛋白α4(ITGA4)和细胞间黏附分子1(ICAM-1)基因的多态性与克罗恩病(CD)的发病风险及临床病理特征之间的相关性。 方法 收集2010年1月至2021年1月于温州医科大学附属第二医院消化内科确诊的215例CD患者及性别、年龄相匹配的529名正常对照者。应用基质辅助激光解吸电离-时间飞行质谱技术检测ITGA4(rs6740847、rs7562325)和ICAM-1(rs5498)的基因型。采用Harvey-Bradshaw指数(HBI)评估CD的疾病活动度，并依据蒙特利尔CD表型分类标准将CD患者分层。采用非条件Logistic回归分析ITGA4(rs6740847、rs7562325)和ICAM-1(rs5498)基因多态性在CD组和正常对照组之间的分布差异及其对CD临床病理特征的影响。 结果 CD组ITGA4(rs7562325)的变异等位基因(T)和变异基因型(CT＋TT)的频率均高于正常对照组(40.70% vs. 31.57%，P＝0.001；62.79% vs. 54.36%，P＝0.042)。中重度活动期CD患者ITGA4(rs6740847)的变异等位基因(G)和变异基因型(AG＋GG)的频率均低于轻度活动期CD患者(31.18% vs. 51.72%，P＝0.002；55.91% vs. 75.86%，P＝0.042)；中重度活动期CD患者ICAM-1(rs5498)的变异等位基因(G)和变异基因型(AG＋GG)的频率均高于轻度活动期CD患者(31.45% vs. 17.24%，P＝0.027；54.30% vs. 31.04%，P＝0.020)。与(回肠末端型＋回结肠型)CD患者比较，结肠型CD患者ITGA4(rs6740847)的变异等位基因(G)和变异基因型(AG＋GG)的频率显著偏高(55.26% vs. 29.38%，P<0.000 1；84.21%vs. 53.11%，P<0.000 1)，ICAM-1(rs5498)的变异等位基因(G)和变异基因型(AG＋GG)的频率亦显著偏高(42.11% vs. 26.84%，P＝0.008；73.69% vs. 46.33%，P＝0.002)。(狭窄型＋穿透型)CD患者ICAM-1(rs5498)的纯合变异基因型(GG)频率低于非狭窄非穿透型CD患者(0.00% vs. 12.32%，P＝0.001)。合并肛周病变的CD患者ITGA4(rs6740847)的变异等位基因(G)和变异基因型(AG＋GG)的频率均高于无肛周病变的CD患者(40.28% vs. 30.77%，P＝0.049；72.22% vs. 51.75%，P＝0.004)。 结论 ITGA4(rs7562325)基因变异可能是CD发病的风险因素。ITGA4(rs6740847)基因变异可能与CD疾病活动度降低相关，却可能是结肠受累和肛周病变的风险因素。ICAM-1(rs5498)基因变异可能是CD疾病活动度增加和结肠受累的风险因素，却可能是狭窄或穿透的保护因素。此外，ITGA4(rs6740847)基因变异和ICAM-1(rs5498)基因变异可能均与CD疾病早发相关。 Objective To assess the association between the polymorphisms of integral protein α4 ( ITGA4) and intercellular adhesion molecule 1 (ICAM-1) genesand the risk and clinicopathological characteristics of Crohn′s disease (CD) among Chinese patients. Methods From January 2010 to January 2021, a total of 215 CD patients and 529 gender- and age-matched healthy controls were enrolled from the Second Affiliated Hospital of Wenzhou Medical University as the study subjects. Genotypes of ITGA4 (rs6740847, rs7562325) and ICAM-1 (rs5498) were determined by matrix-assisted laser desorption ionization-time of flight mass spectrometry. Harvey-Bradshaw Index (HBI) was applied to assess the disease activity of CD, and the patients were further divided into subgroups based on the Montreal Classification Criteria of CD. Unconditional logistic regression was employed to analyze the distribution of ITGA4 (rs6740847, rs7562325) and ICAM-1 (rs5498) polymorphisms between the patients and healthy controls and their association with the clinicopathological characteristics of the patients. Results The frequencies of T allele and CT+ TT genotypes of ITGA4 (rs7562325) were higher in CD patients than the healthy controls (40.70% vs. 31.57%, P=0.001 62.79% vs. 54.36%, P=0.042). The G variant and AG+ GG genotypes of ITGA4 (rs6740847) were less common in patients with moderately to severely active CD compared with those with mildly active CD (31.18% vs. 51.72%, P=0.002 55.91% vs. 75.86%, P=0.042). However, the opposite conclusion was drawn for the G allele (G) and AG+ GG genotypes of ICAM-1 (rs5498) (31.45% vs. 17.24%, P=0.027 54.30% vs. 31.04%, P=0.020). Compared with patients with terminal ileal or ileocolic CD, G allele and AG+ GG genotypes of ITGA4 (rs6740847) were more prevalent in patients with colonic CD (55.26% vs. 29.38%, P<0.000 1 84.21%vs. 53.11%, P<0.000 1). The same conclusion could also be drawn for the G allele and AG+ GG genotypes ofICAM-1 (rs5498) (42.11% vs. 26.84%, P=0.008 73.69% vs. 46.33%, P=0.002). The frequency of homozygous GG genotype of ICAM-1 (rs5498) was lower in patients with stricturing and penetrating CD than those with non-stricturing and non-penetrating CD (0.00% vs. 12.32%, P=0.001). The G allele and AG+ GG genotypes of the ITGA4 (rs6740847) were more common in patients with perianal lesions than those without (40.28% vs. 30.77%, P=0.049 72.22% vs. 51.75%, P=0.004). Conclusion Variants of the ITGA4 (rs7562325) may be a risk factor for CD, whilst those of the ITGA4 (rs6740847) may be associated with the decline of disease activity and risk for colon involvement and perianal lesions. Variants of the ICAM-1 (rs5498) may increase the risk of disease activity and colonic involvement in CD patients, however, it may be a protective factor for stenosis and penetration. In addition, variants of the ITGA4 (rs6740847) and ICAM-1 (rs5498) may be associated with the early onset of CD.

    克罗恩病整联蛋白α4细胞间黏附分子1基因多态性

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    脊髓性肌萎缩伴呼吸窘迫1型二家系的 IGHMBP2基因变异分析和产前诊断

    李慧君朱湘玉杨滢吴星...
    167-173页
    查看更多>>摘要：目的 探究2个脊髓性肌萎缩伴呼吸窘迫1型(SMARD1)家系的遗传学病因，并预防出生缺陷。 方法 选取2021年8月至11月于南京大学医学院附属鼓楼医院妇产医学中心就诊的2个无亲缘关系的家系为研究对象。运用多重连接依赖探针扩增技术(MLPA)检测先证者及其家系成员SMN1基因第7外显子的拷贝数，通过全外显子组测序(WES)对先证者进行基因检测，并对家系成员行Sanger测序验证分析，对变异位点进行生物信息学分析。依据上述检测与分析结果，对家系中再次妊娠的胎儿行介入性产前诊断。 结果 基因检测发现2例先证者均携带IGHMBP2基因复合杂合变异，分别遗传自父母。其中变异c.1144C>T、c.866delG和c.1666C>G既往未见报道，根据美国医学遗传学与基因组学学会变异相关指南分别评为致病性变异(PVS1＋PM2_Supporting＋PP3＋PP4)、可能致病性变异(PM1＋PM2_Supporting＋PM4＋PP3＋PP4)和可能致病性变异(PM1＋PM2_Supporting＋PP2＋PP3＋PP4)。通过胚胎植入前单基因遗传学检测(PGT-M)和介入性产前诊断成功阻断了变异在家系中的传递，有效预防了出生缺陷的发生。 结论 该2例考虑是由IGHMBP2基因复合杂合变异导致的SMARD1，为SMARD1的鉴别诊断和家系遗传咨询提供重要依据。 Objective To explore the genetic etiology of two children with Spinal muscular atrophy with respiratory distress type 1 (SMARD1), and prevent the recurrence of birth defects. Methods Two unrelated families who had visited the Obstetrics and Gynecology Medical Center of Drum Tower Hospital from August to November 2021 were selected as the study subjects. Copy number of SMN1 gene exon 7 for the probands and their parents was detected by multiple ligation-dependent probe amplification (MLPA). and whole exome sequencing (WES) was carried out to screen the variants in the probands. Sanger sequencing was used to validate the variants within the families. Pathogenecity of the variants were predicted by bioinformatic analysis. Based on the results, prenatal diagnosis was performed for the fetuses. Results Both probands were found to harbor compound heterozygous variants of the IGHMBP2 gene, which were inherited from their parents. Among these, c. 1144C>T, c. 866delG and c. 1666C>G were previously unreported and respectively classified as pathogenic variant (PVS1+ PM2_Supporting+ PP3+ PP4), likely pathogenic variant (PM1+ PM2_Supporting+ PM4+ PP3+ PP4) and likely pathogenic variant (PM1+ PM2_Supporting+ PP2+ PP3+ PP4) based on the ACMG guidelines. Through preimplantation genetic testing for monogenic (PGT-M) and interventional prenatal diagnosis, transmission of the variants within the families was successfully blocked. Conclusion The SMARD1 in both children may be attributed to the compound heterozygous variants of the IGHMBP2 gene, which has facilitated the genetic diagnosis and counselling, and provided reference for delineating the molecular pathogenesis of this disease.

    脊髓性肌萎缩伴呼吸窘迫1型IGHMBP2基因产前诊断

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    SCN8A基因变异致癫痫5例患儿的临床特征及遗传学分析

    张新邱世彦杨莉李玉芬...
    174-180页
    查看更多>>摘要：目的 探讨5例SCN8A基因变异所致癫痫患儿的临床及遗传学特点。 方法 收集2015年8月至2022年8月在临沂市人民医院拟诊为遗传性癫痫患儿的临床资料，对其进行家系全外显子组测序，对候选变异进行Sanger测序家系验证。 结果 共筛选出5例(4男1女)携带SCN8A变异的患儿。患儿1具有良性家族性婴儿癫痫，携带遗传自父亲(具有相似表型)的c.4840A>G变异，为已报道致病性变异。患儿2～4为中间型癫痫。患儿2携带c.3967G>A新发变异，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(PS1＋PS2＋PM1＋PM2_Supporting＋PP3)，患儿3携带c.415A>T变异，患儿4携带c.4697C>T新发变异，均评级为可能致病性变异(PS2＋PM1＋PM2_Supporting＋PP3)。患儿5具有早期婴儿癫痫性脑病，之后转变为类Lennox-Gastaut综合征，携带c.5615G>A新发变异，为已报道致病性变异。5例患儿的首次发病年龄为2 ～ 14个月，均存在局灶性发作和全面强直阵挛发作，患儿1、2、3、5具有丛集性发作的特点，患儿1 ～ 4单药或双药治疗后发作得到控制，生长发育正常，患儿5属于药物难治性癫痫，且存在严重的发育落后。 结论 上述5例癫痫患儿均存在成簇发作、良性癫痫成年期偶尔发作、中间型癫痫停药易复发的新特点，SCN8A基因变异考虑为其致病原因。 Objective To explore the clinical and genetic characteristics of five children with epilepsies due to variants of SCN8A gene. Methods Clinical data of five children (four males and one female) admitted to Linyi People′s Hospital due to hereditary epilepsies between August 2015 and August 2022 were collected. Whole exome sequencing was carried out for these children, and candidate variants were verified by Sanger sequencing. Results All of the five children were found to harbor variants of the SCN8A gene. Case 1, who had benign familial infantile epilepsy, inherited a known pathogenic c. 4840A>G variant from his father with similar symptoms. Cases 2 to 4 had presented with intermediate epilepsy. Among these, case 2 has harbored ade novo c. 3967G>A variant which was rated as pathogenic (PS1+ PS2+ PM1+ PM2_Supporting+ PP3) based on the guidelines from the American College of Medical Genetics and Genomics. Cases 3 and 4 were found to respectively harbor ade novo c. 415A>T and a c. 4697C>T variant, which were both rated as likely pathogenic (PS2+ PM1+ PM2_Supporting+ PP3). Case 5, who had early-onset infantile epileptic encephalopathy transformed into Lennox Gastaut-like syndrome, has harbored ade novo c. 5615G>A variant, which was known to be pathogenic. The children had their age of onset ranging from 2 to 14 months, and all had focal seizures and generalized tonic clonic seizures. Four children (cases 1, 2, 3 and 5) had cluster seizures, four (cases 1 to 4) had become seizure-free after single or dual treatment and showed normal growth and development, whilst case 5 was drug-resistant and showed severe developmental retardation. Conclusion The five children had new features such as cluster seizures, occasional benign seizures in adulthood, and intermediate epilepsy which are prone to relapse after discontinuation of medication, which may be attributed to the pathogenic variants of the SCN8A gene.

    SCN8A基因癫痫全外显子组测序基因变异

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    FOXP3基因变异致X连锁多内分泌腺病肠病伴免疫失调综合征3例患儿的临床及遗传学研究

    郑翠芳孟颖颖邓朝晖刘静...
    181-186页
    查看更多>>摘要：目的 分析3例X连锁多内分泌腺病肠病伴免疫失调(IPEX)综合征患儿的临床特点及基因变异情况。 方法 总结复旦大学附属儿科医院2013年1月24日至2019年7月29日收治的3例IPEX综合征患儿的临床特点、实验室检查与基因检测的结果、治疗及预后的情况。 结果 3例患儿均于婴幼儿期起病，其中1例以糖尿病伴酮症酸中毒为首发症状，2例以腹泻起病。3例患儿均有消化道受累的表现，其中1例经内镜及病理检查诊断为极早发炎症性肠病。3例患儿中有2例合并内分泌腺受累，其中1例表现为1型糖尿病伴甲状腺球蛋白及甲状腺过氧化物酶抗体阳性，但随访未发现甲状腺功能异常；另1例表现为甲状腺功能低下，予左旋甲状腺素治疗。3例患儿均携带FOXP3基因错义变异，包括c.1222G>A(p.V408M)、c.767T>C(p.M256T)和c.1021A>G(p.T341A)。1例经异基因造血干细胞移植治疗后症状缓解，1例予生物制剂加胰岛素治疗后病情稳定，另1例出生后3个月因难治性脓毒性休克及多器官功能衰竭夭折。 结论 FOXP3基因变异相关的IPEX综合征可能具有起病早、临床表现多样的特点。对于婴幼儿期起病的慢性腹泻伴多内分泌腺或多系统受累的男性患儿，需警惕IPEX综合征的可能性，尽早通过基因检测进行诊断和治疗，并为遗传咨询提供依据。 Objective To analyze the clinical characteristics of three patients with Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Methods Three patients with IPEX syndrome diagnosed at the Children′s Hospital of Fudan University from January 24, 2013 to July 29, 2019 were selected as the study subjects. Their clinical features, laboratory investigations and results of genetic testing were summarized. Treatment and prognosis were also explored. Results All of the three children had developed the disorder during infancy. One child had initial features including diabetes and diabetic ketoacidosis, whilst the other two had initiated by diarrhea. All patients had gastrointestinal involvement, and one was diagnosed as very early onset inflammatory bowel disease by colonoscopy and biopsy. Two children also had endocrine glands involvement. One child had manifested type 1 diabetes and positivity for thyroglobulin and thyroid peroxidase antibodies, though his thyroid function had remained normal. Another one had hypothyroidism and was treated by levothyroxine. Genetic testing revealed that all children had harbored missense variants of the FOXP3 gene, including c. 1222G>A (p.V408M), c. 767T>C (p.M256T) and c. 1021A>G (p.T341A). The clinical symptoms of one patient were alleviated following allogeneic hematopoietic stem cell transplantation. One patient was stable after treatment with infliximab plus insulin, and one child had died of refractory septic shock and multiple organ dysfunction syndrome at 3 months old. Conclusion FOXP3 gene variant-associated IPEX syndrome may have very early onset and diverse clinical manifestations. For male patients with infantile onset chronic diarrhea, multiple endocrine or multiple system involvement, genetic testing is recommended, which may facilitate early diagnosis, treatment and genetic counseling.

    X连锁多内分泌腺病肠病伴免疫失调综合征FOXP3基因极早发炎症性肠病糖尿病

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    TUBB2A基因新发变异导致癫痫伴发育迟缓及脑发育畸形一个家系的遗传学分析

    赵娟徐那李玉芬杨莉...
    187-192页
    查看更多>>摘要：目的 探究1个癫痫伴发育迟缓及脑发育畸形家系的临床表现及致病基因变异情况。 方法 选取2022年7月2日于临沂市人民医院儿内科就诊的1个癫痫伴发育迟缓及脑发育异常家系为研究对象。收集患儿及其家系成员的临床资料，应用高通量测序技术对患儿及其姐姐与父母进行基因检测，采用Sanger测序法进行验证。 结果 患儿为6岁男性，自幼全面生长发育迟缓，间断抽搐4年余，癫痫发作存在热敏感特点，头颅影像学提示脑发育畸形，视频脑电图提示异常放电。高通量测序结果显示患儿及其姐姐均携带TUBB2A基因c.5G>T(p.Arg2Leu)杂合变异，其父母为野生型。根据美国医学遗传学与基因组学学会(ACMG)相关标准及指南，该变异评定为致病性变异(PS2＋PM2_Supporting＋PM5＋PP1＋PP2＋PP3)。 结论 TUBB2A基因c.5G>T(p.Arg2Leu)杂合变异考虑是该家系的遗传学病因，可能存在生殖腺细胞嵌合的情况。 Objective To explore the clinical manifestations and pathogenic variant in a family with epilepsy, developmental delay and brain deformity. Methods Clinical data of the child and his family members who had visited the Department of Pediatrics, Linyi People's Hospital on July 2, 2022 were collected. The child, his sister and parents were subjected to high-throughput sequencing, and the result was verified by Sanger sequencing. Results The child was a 6-year-old boy with developmentally delay and had epileptic seizures with fever sensitivity for four years. Cranial imaging showed brain dysplasia, while the video electroencephalogram showed abnormal discharge. High-throughput sequencing showed the child has harbored a heterozygous c. 5G>T (p.Arg2Leu) variant ofTUBB2A gene, which was unreported previously. His sister also carried the variant and had similar clinical manifestations, whilst his parents were of the wild-type and had normal clinical phenotypes. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as pathogenic (PS2+ PM2_Supporting+ PM5+ PP1+ PP2+ PP3). Conclusion The heterozygous c. 5G>T (p.Arg2Leu) variant of theTUBB2A gene, in the form of gonadal mosaicism, probably underlay the disorders in this family.

    TUBB2A癫痫发育迟缓脑发育畸形

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