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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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    VPS13B基因复合杂合变异致Cohen综合征一个家系的遗传学分析

    张闻宇祁娜郭梁洁王红丹...
    966-972页
    查看更多>>摘要：目的 分析1个Cohen综合征家系的临床表型与遗传学特征，并为产前诊断提供实验依据。 方法 选取2021年6月2日因"智力障碍及发育迟缓"就诊于郑州人民医院的Cohen综合征女性先证者、先证者妹妹及其家系成员(3代共11人)作为研究对象，收集先证者及先证者妹妹的临床资料。提取该家系成员外周血样品及胎儿胎盘绒毛样品基因组DNA，利用染色体微阵列技术(CMA)检测先证者染色体异常情况。利用全外显子组测序(WES)及Sanger测序，寻找先证者候选变异位点，并进行家系验证。提取家系成员外周血RNA，进行体内剪接变异体检测，应用RT-PCR分析VPS13B基因的mRNA表达水平，并对胎龄12周的胎儿的进行产前诊断。 结果 先证者为10岁女性，临床表现为发育迟缓、躯体肥胖、高度近视、特殊面容。先证者妹妹为3岁女性，具有与先证者相同表型。CMA结果提示先证者染色体未见异常。WES结果发现先证者及其妹妹VPS13B基因存在2个杂合变异，分别为c.10076_10077delCA(p.T3359fs*29)缺失移码变异及c.6940+1G>T剪接位点变异，均已有报道。母亲为c.10076_10077delCA(p.T3359fs*29)变异携带者，遗传自先证者外祖父。父亲为c.6940+1G>T变异携带者，遗传自先证者祖母。根据美国医学遗传学与基因组学学会遗传变异分类标准与指南，c.10076_10077delCA评级为致病性变异(PVS1+PS4+PM4+PP1)，c.6940+1G>T评级为致病性变异(PVS1+PM2_Supporting+PM3+PP1)。c.6940+1G>T剪接位点变异导致VPS13B基因第38外显子发生跳跃，产生1个缺失69个氨基酸的转录本。与对照组相比，先证者父母在外周血中mRNA表达水平降低至65%~70%(P<0.01)、先证者及其妹妹降低至40%(P<0.001)。对胎龄12周的胎儿的产前诊断发现胎儿存在c.10076_10077delCA杂合变异。 结论 VPS13B基因的c.10076_10077delCA(p.T3359fs*29)缺失移码变异及c.6940+1G>T剪接位点变异考虑为该家系先证者及其妹妹患Cohen综合征的致病原因。基因检测技术可以辅助临床医师诊断Cohen综合征。 Objective To investigate the clinical phenotype and genetic characteristics of a Chinese pedigree affected with Cohen syndrome. Methods A proband who was admitted to Zhengzhou People′s Hospital on June 2, 2021 due to intellectual disability and developmental delay, in addition with her younger sister and other family members, were selected as the study subjects. The clinical data of the proband and her younger sister were collected. Genomic DNA was extracted from peripheral venous blood and chorionic villi samples. Chromosomal abnormalities were detected with chromosomal microarray analysis (CMA). Whole exome sequencing (WES) and Sanger sequencing were carried out to detect candidate variants in the proband. With RNA extracted from the peripheral blood samples VPS13B gene transcripts and expression were analyzed by PCR and real-time quantitative PCR. Prenatal diagnosis was carried out at 12 weeks′ gestation. Results The proband was a 10-year-old female with clinical manifestations including development delay, obesity, severe myopia and peculiar facial features. Her sister was 3 years old with a similar phenotype. CMA revealed no chromosomal abnormality in the proband, while WES results revealed that the proband and her sister had both harbored compound heterozygous variants of the VPS13B gene, namely c. 10076_10077delCA (p.T3359fs*29) and c. 6940+ 1G>T, which were respectively inherited from their mother and father. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were classified as pathogenic (PVS1+ PS4+ PM4+ PP1 PVS1+ PM2_Supporting+ PM3+ PP1).In vivo splicing assay confirmed that the c. 6940+ 1G>T variant has produced a frameshift transcript with skipping of exon 38. Compared with the control group, the expression of RNA in the peripheral blood of the proband′s parents has decreased to 65%~70% (P< 0.01), whilst that in the proband and her sister has decreased to 40% (P < 0.001). Prenatal diagnosis at 12 weeks of gestation has found that the fetus only harbored the heterozygous c. 10076_ 10077delCA variant. Conclusion The c. 10076_10077delCA (p.T3359fs*29) frameshift variant and c. 6940+ 1G>T splicing variant probably underlay the Cohen syndrome in this pedigree. Genetic testing has facilitated the diagnosis of this disease.

    Cohen综合征VPS13B基因基因变异全外显子组测序家系

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    PAX2基因变异所致慢性肾脏病一个家系的遗传学分析

    马江磊张慧杰王光明梁程红...
    973-978页
    查看更多>>摘要：目的 探讨PAX2基因变异所致的1个慢性肾脏病(CKD)家系的遗传学特征。 方法 选取2018年8月15日至2021年7月5日于大理大学第一附属医院就诊的1个CKD家系4代共10人为研究对象。收集先证者的临床资料，并进行家系调查。应用全外显子组测序(WES)技术和生物信息学分析对先证者进行疑似致病基因筛选，应用Sanger测序进行家系验证。 结果 先证者为女性，年龄为41岁，确诊"慢性肾炎"4+年。尿常规提示尿蛋白(+)，血肌酐1 130 μmol/L，肾穿刺病理结果提示增生硬化性肾小球肾炎、中度肾小管间质病变及肾小动脉硬化。其姐姐、弟弟、妹妹和母亲为CKD 5期患者，除姐姐外均已去世，余家系成员未见异常。基因检测发现先证者及4名家系成员携带PAX2：c.167G>A错义变异。该变异与局灶节段性肾小球硬化相关，根据美国医学遗传学与基因组学学会(ACMG)相关指南评估为可能致病性变异(PS1+PP3+PP4)。 结论 PAX2：c.167G>A变异可能为该CKD家系的遗传学病因。 Objective To explore the genetic basis of a Chinese pedigree affected with chronic kidney disease (CKD). Methods A Chinese pedigree comprised of 10 individuals from four generation who had visited the First Affiliated Hospital of Dali University from August 15, 2018 to July 5, 2021 was selected as the study subject. Clinical data of the proband were collected, and a pedigree survey was conducted. The proband was subjected to whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing and bioinformatic analysis. Results The proband, a 41-year-old female, has been diagnosed with chronic nephritis for more than 4 years. Routine urinary examination showed urine protein (+ ) and blood creatinine of 1 130 μmol/L. Renal puncture revealed hyperplastic glomerulonephritis, moderate tubulointerstitial disease and renal arteriosclerosis. Her elder sister, younger brother, younger sister and mother were all diagnosed with CKD stages. Except for her elder sister, all of them had deceased, and no abnormality was found in the remainders. Genetic testing revealed that the proband and four family members had harbored a c. 467G>A missense variant of the PAX2 gene. The variant has been associated with focal segmental glomerulosclerosis and classified as likely pathogenic (PS1+ PP3+ PP4) based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). Conclusion The c. 167G>A variant of thePAX2 gene probably underlay the CKD in this Chinese pedigree.

    高通量测序PAX2基因慢性肾脏病产前诊断

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    新生儿严重甲状旁腺功能亢进症患儿2例的临床特征及遗传学分析

    荀泽丽汪治华杜亚楠刘超...
    979-985页
    查看更多>>摘要：目的 探讨新生儿严重甲状旁腺功能亢进症(NSHPT)患儿的临床特征及基因变异特点。 方法 选择分别于2019年8月与2022年4月在西安交通大学附属儿童医院内分泌遗传代谢科被确诊为NSHPT的患儿1、2为研究对象。采取回顾性分析方法，分析其临床病例资料，采用全外显子组测序(WES)进行基因变异检测，采用Sanger测序对候选致病变异进行家系验证结果。 结果 患儿1、2主要临床特征均为生长发育迟缓、肌张力减低、高钙血症、低磷血症、高甲状旁腺激素(PTH)血症、肾脏钙盐沉积。WES结果显示患儿1存在CASR基因c.1378-1G>A纯合剪接变异，为迄今尚未见文献报道的致病性变异；患儿2存在CASR基因c.2038C>T纯合错义变异，为已被文献报道的可能致病性变异。Sanger测序结果显示患儿1父母均携带CASR基因c.1378-1G>A杂合变异，患儿2父母均携带CASR基因c.2038C>T杂合变异。 结论 2例NSHPT患儿分别存在CASR基因c.1378-1G>A、CASR基因c.2038C>T纯合变异，可能为导致其发生NSHPT的遗传学病因。NSHPT患儿1存在的c.1378-1G>A新变异，进一步拓展了该病患儿的CASR基因的变异谱。 Objective To explore the clinical features and genetic variants in two children with neonatal severe hyperparathyroidism (NSHPT). Methods Two children who were diagnosed with NSHPT at the Children′s Hospital Affiliated to Xi′an Jiaotong University respectively in August 2019 and April 2022 were selected as the study subjects. Clinical data were collected, and both children were subjected to whole exome sequencing (WES). Candidate variants were verified by Sanger sequencing. Results The main clinical features of the two children have included growth delay, hypotonia, hypercalcemia, hypophosphatemia, hyperparathyroid hormonemia, and renal calcium deposition. WES results showed that child 1 has harbored a homozygous c. 1378_1G>A splicing variant of theCASR gene, which was unreported previously, whilst child 2 has a harbored homozygous c. 2038C>T missense variant of theCASR gene, which was known to be likely pathogenic. Sanger sequencing confirmed that the parents of both children were heterozygous carriers. Conclusion The homozygous c. 1378_1G>A and c. 2038C>T variants of theCASR gene probably underlay the NSHPT in the two children. Discovery of the c. 1378_1G>A variant has enriched the mutational spectrum of theCASR gene.

    甲状旁腺功能亢进症CASR基因基因变异高钙血症新生儿

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    亚硫酸盐氧化酶缺乏症患儿1例的临床特点及基因变异分析

    杨志刚权亚丽王媛陈国洪...
    986-989页
    查看更多>>摘要：目的 对1例亚硫酸盐氧化酶缺乏症(ISOD)患儿的临床特征及基因变异进行分析，明确其可能的致病原因。 方法 选取在2019年3月就诊于河南省儿童医院的1例患儿作为研究对象。采用目标区域捕获对患儿及父母进行全外显子组测序，按照美国医学遗传学与基因组学学会(ACMG)的基因变异解读标准和指南对基因变异进行致病性评估。 结果 基因检测结果显示患儿SUOX基因存在c.1200C>G(p.Tyr400*)和c.1406_1421delCCTGGCAGGTGGCTAA(p.Thr469Serfs*20)复合杂合变异，患儿母亲携带c.1200C>G(p.Tyr400*)杂合变异，父亲携带c.1406_1421delCCTGGCAGGTGGCTAA(p.Thr469Serfs*20)杂合变异。其中c.1200C>G为已报道过的致病性变异，而c.1406_1421del CCTGGCAGGTGGCTAA未见报道，根据ACMG变异解读标准和指南，该变异判定为致病性变异(PVS1+PM2_Supporting+PM3)。 结论 SUOX基因c.1200C>G和c.1406_1421delCCTGGCAGGTGGCTAA变异可能为该例ISOD患儿的致病原因，本研究扩展了SUOX基因变异谱，为患儿的临床诊断及该家系的遗传咨询提供了依据。 Objective To explore the genetic basis for a child with Isolated sulfite oxidase deficiency(ISOD). Methods The child and her parents were subjected to targeted capture and next-generation sequencing. Pathogenicity of candidate variants was assessed based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). Results The child was found to harbor compound heterozygous variants of the SUOX gene, namely c. 1200C>G (p.Tyr400*) and c. 1406_1421delCCTGGCAGGTGGCTAA (p.Thr469Serfs*20), which were inherited from her mother and father, respectively. The c. 1200C>G was a known pathogenic variant, while c. 1406_1421delCCTGGCAGGTGG CTAA was unreported previously and predicted to be a pathogenic variant (PVS1+ PM2_Supporting+ PM3) based on the guidelines from the American College of Medical Genetics and Genomics. Conclusion The compound c. 1200C>G and c. 1406_1421delCCTGGCAGGTGGCTAA variants of theSUOX gene probably underlay the pathogenesis of ISOD in this child. Above finding has expanded the spectrum of SUOX gene variants and provided molecular evidence for the clinical diagnosis and genetic counseling for this pedigree.

    亚硫酸盐氧化酶缺乏症SUOX基因缺血缺氧性脑病基因变异

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    限制型心肌病合并苯丙酮尿症患儿1例的遗传学分析及文献回顾

    王芳洁肖梦君孙琪青贾丽娟...
    990-997页
    查看更多>>摘要：目的 分析1例罕见的儿童限制型心肌病合并苯丙酮尿症(PKU)患儿的临床及基因变异，通过文献回顾总结儿童限制型心肌病的临床特点及遗传学分析。 方法 选取2020年6月因"双眼睑及双下肢水肿1年，加重1月余"就诊于郑州大学附属儿童医院的1例限制型心肌病合并PKU患儿作为研究对象，并收集其临床相关资料。采集患儿及父母外周血样，进行全外显子组测序(WES)确定候选位点，Sanger测序进行验证确定变异位点，生物信息学软件分析变异致病性。以"儿童期发病""TNNI3基因""限制型心肌病"为关键词，在万方数据知识服务平台、中国期刊全文数据库中设定检索年限为建库至2022年8月检索中文文献。并以"childhood""TNNI3 gene""restrictive cardiomyopathy"为关键词在生物医学文献数据库(PubMed)中设定检索年限为建库至2022年8月搜索外文文献，总结其临床表现和TNNI3基因变异特点。 结果 患儿为2岁4月龄男性，智力正常，运动、体格发育落后，未见特殊面容，头发和皮肤色泽未见明显异常，双眼睑及下肢浮肿。WES及Sanger测序结果提示患儿PAH基因存在父源的c.331C>T(p.R111X)和母源的c.940C>A(p.P341T)复合杂合变异。同时患儿TNNI3基因存在新发杂合变异c.508C>T(p.R170W)，父亲和母亲未见该变异。依据美国医学遗传学与基因组学学会变异评级相关指南，TNNI3：c.508C>T(p.R170W)评级为致病性变异(PS2+PS4+PM2_Supporting+PM5)，PAH：c.331C>T(p.R111X)评级为致病性变异(PVS1+PM2_Supporting+PM3+PP4)，c.940C>A(p.P341T)评级为可能致病性变异(PM2_Supporting +PM3+PM5+PP4)。按检索限定共检索到TNNI3基因变异所致儿童期发病的限制型心肌病30例，男女比例约1：1.55，表现为心力衰竭、窦性心律、双心房增大、ST-T波改变、心室限制型充盈、心室舒张功能下降等。30例共发现TNNI3基因16种不同变异位点，其中c.575G>A最常见，均符合常染色体显性遗传方式。 结论 苯丙氨酸羟化酶缺乏症与限制性心肌病均为罕见病，临床表现复杂。基因检测技术发现该患儿存在PAH：c.331C>T(p.R111X)/c.940C>A(p.P341T)复合杂合变异及TNNI3：c.508C>T(p.R170W)变异，考虑是共患限制型心肌病及PKU的原因。 Objective To analyze the clinical and genetic characteristics of a child with restricted cardiomyopathy (RCM) and phenylketonuria (PKU), and summarize the clinical characteristics and genetic diversity of RCM in children through a literature review. Methods A child with RCM in conjunct with PKU who was admitted to the Children′s Hospital Affiliated to Zhengzhou University on June 2020 due to edema of eyelids and lower limbs for 1 year and aggravation for over 1 month was selected as the study subject. Relevant clinical data were collected. Peripheral blood samples of the child and his parents were collected for whole exome sequencing (WES). Candidate variants were validated by Sanger sequencing and bioinformatic analysis. Childhood, TNNI3 gene and restricted cardiomyopathy were used as the keywords to search the Wanfang data knowledge service platform, Chinese Journal Full-text database and PubMed database, and the search period was limited to from the time of establishment till August 2022. Clinical manifestations and characteristics of the TNNI3 gene variants were summarized. Results The child, a 2-year-old-and-4-month-old male, had normal intelligence, facial features and normal hair and skin color, but his motor and physical development was delayed, in addition with edema of bilateral eyelids and lower limbs. The results of WES and Sanger sequencing revealed that he has harbored compound heterozygous variants of the PAH gene, namely c. 331C>T (p.R111X) and c. 940C>A (p.P341T), which were inherited from his father and mother, respectively. In addition, he has also harbored ade novo heterozygous variant of c. 508C>T (p.R170W) of theTNNI3 gene. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the TNNI3: c. 508C>T (p.R170W) was classified as a pathogenic variant (PS2+ PS4+ PM2_Supporting+ PM5),PAH: c. 331C>T (p.R111X) as pathogenic variant (PVS1+ PM2_Supporting+ PM3+ PP4), and c. 940C>A (p.P341T) as a likely pathogenic variant (PM2_Supporting+ PM3+ PM5+ PP4). In total 30 children with RCM caused byTNNI3 gene variants were retrieved, with a male-to-female ratio of 1 : 1.55 and manifestations including heart failure, sinus rhythm, bi-atrial enlargement, ST-T wave change, ventricular restricted filling, and decreased ventricular diastolic function. In total 16 variants of the TNNI3 gene were identified, among which c. 575G>A was the most common, and all cases had conformed to an autosomal dominant inheritance. Conclusion Phenylalanine hydroxylase deficiency and RCM are rare diseases with complex clinical manifestations. PAH: c. 331C>T (p.R111X)/c.940C>A (p.P341T) andTNNI3: c. 508C>T (p.R170W) variants probably underlay the RCM and PKU in this child.

    苯丙酮尿症限制型心肌病PAH基因TNNI3基因基因变异儿童

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    产前诊断Xq21.1q21.31微重复1例

    吕欣岳发贵刘睿智何晶...
    997页
    查看更多>>摘要：31岁，G3P1，健康状况良好，否认不良接触史、家族遗传病史、传染病史及手术史，系非近亲婚配。12岁时月经初潮，月经周期28~30 d，经期规律。中孕期唐氏血清学筛查提示临界风险，孕19周孕妇无创产前检测提示性染色体异常，于2019年10月24日就诊于吉林大学第一医院。本研究通过了上述医院伦理委员会审查(2021-395)，患者及其丈夫签署了知情同意书。孕妇羊水染色体核型为46，X，dup(X)(q21.1q21.3)(图1)，羊水染色体微阵列检测提示arr[GRCh37]Xq21.1q21.31(84320022-91308217)×3，即X染色体长臂q21.1q21.31区存在约6.98 Mb重复(图2)。孕妇染色体核型为46，X，dup(X)(q21.1q21.3)，丈夫未见异常，提示胎儿X染色体重复区域遗传自胎儿母亲。该重复区域包含ZNF711、POF1B、CHM等9个OMIM基因，ClinGen数据库显示无基因三倍剂量敏感性证据，DGV数据库、DECIPHER数据库均未收录相似变异的报道，该重复片段致病性判断为临床意义不明。经遗传咨询，夫妇选择继续妊娠，于孕39周娩出1女婴，体质量为3.2 kg，身长50 cm，暂未见先天畸形等异常情况。
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    SPECC1L基因变异所致Teebi眼距过宽综合征患儿1例

    李智颖王依柔李辛冯碧云...
    998-1003页
    查看更多>>摘要：目的 探讨1例SPECCIL基因变异所致Teebi眼距过宽综合征1(TBHS1)患儿的临床特点及其致病机制。 方法 选取2021年7月13日于上海交通大学医学院附属儿童医学中心内分泌与遗传代谢科就诊的1例TBHS1患儿为研究对象。回顾分析患儿的临床资料，抽取患儿及其父母的外周静脉血样，采用全外显子组测序(WES)对患儿进行分析，针对候选变异进行Sanger测序家系验证与生物信息学分析。 结果 患儿为13岁男性，临床表现为生长发育迟缓。WES检测结果提示患儿SPECC1L基因存在c.1244A>G杂合变异，Sanger测序验证为新发变异。该变异在HGMD与gnomAD等数据库中均未见收录；经PolyPhen-2、SIFT及Mutation Taster等在线软件预测，该变异可能影响蛋白结构域功能；经PyMOL软件预测，变异型SPECC1L蛋白(p.Gln415Arg)结构稳定性可能降低；参照美国医学遗传学与基因组学学会(ACMG)相关标准与指南，该变异被评级为致病性变异(PM6+PM1+PP4+PM2_Supporting+PP3)。 结论 SPECC1L基因c.1244A>G杂合变异可能是该TBHS1患儿的遗传学病因。该变异的发现拓展了SPECC1L基因的变异与表型谱，为临床诊断该类患儿提供了更多的参考依据。 Objective To explore the clinical characteristics and genetic basis of a child with Teebi hypertelorism syndrome 1 (TBHS1). Methods A child with TBHS1 who was admitted to the Children′s Medical Center Affiliated to Shanghai Jiao Tong University School of Medicine on July 13, 2021 was selected as the study subject. Clinical data of the child was collected. 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 and bioinformatic analysis. Results The child, a 13-year-old male, had manifested delayed growth and development. WES results revealed that he has harbored a heterozygous c. 1244A>G variant of theSPECC1L gene, which was verified to be de novo in origin. The variant has not been included in the HGMD and gnomAD databases. As predicted by online software including PolyPhen-2, SIFT, and Mutation Taster, the variant may affect the function of protein domain. And PyMOL software has predicted that the structural stability of SPECC1L protein (p.Gln415Arg) might be reduced. Based on the guidelines of the American College of Medical Genetics and Genomics (ACMG), the variant was classified as pathogenic (PM6+ PM1+ PP4+ PM2_Supporting+ PP3). Conclusion The heterozygous c. 1244A>G variant of theSPECC1L gene probably underlay the TBHS1 in this child. Above finding has expanded the genotypic and phenotypic spectrum of the SPECC1L gene and provided a basis for the clinical diagnosis of this child.

    Teebi眼距过宽综合征1发育迟缓SPECC1L基因青少年

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    低镁血症、癫痫和智力障碍综合征患儿1例的 CNNM2基因变异分析

    王琳张洪伟罗俊霞亓芳...
    1004-1008页
    查看更多>>摘要：目的 探讨1例儿童低镁血症、癫痫和智力障碍(HSMR)综合征患者的分子遗传学病因。 方法 选取2021年7月9日因"反复抽搐2个月"收治于山东大学附属儿童医院的HSMR综合征患儿作为研究对象，并收集其临床资料。采集患儿及父母的外周血样，提取基因组DNA，应用全外显子组测序技术进行基因检测，确定候选变异位点，Sanger测序家系验证。应用生物信息学分析软件SWISS-MODEL对蛋白质结构模型进行预测。 结果 患儿为男性，就诊时为1岁7月龄，临床表现为癫痫发作、全面性发育迟缓，血清学检测提示低血清镁。基因检测结果提示患儿CNNM2基因存在c.1448delT (p.Val483GlyfsTer29)杂合变异，考虑为新发变异。该变异使CNNM2基因第1 448位核苷酸T发生缺失，导致第483位氨基酸由缬氨酸变成甘氨酸，且下游第29位氨基酸变为终止密码子。SWISS-MODEL软件分析提示该变异位点导致蛋白结构发生改变，产生截短蛋白。根据美国医学遗传学与基因组学学会遗传变异与分类指南，c.1448del T (p.Val483GlyfsTer29)评级为致病性变异(PVS1+PS2+PM2_Supporting+PP4)。 结论 CNNM2基因c.1448delT杂合变异考虑为HSMR综合征患儿的致病原因，该变异的发现丰富了CNNM2基因表型-基因型。 Objective To explore the genetic etiology of a child with Hypomagnesemia, epilepsy and mental retardation syndrome (HSMR). Methods A child who was admitted to the Children′s Hospital of Shandong University on July 9, 2021 due to repeated convulsions for 2 months was selected as the study subject. Clinical data of the child was collected. Peripheral blood samples of the child and his pedigree members were collected for the extraction of genomic DNA. Whole exome sequencing was carried out, and candidate variant was verified by Sanger sequencing and bioinformatic analysis. Results The child, a 1-year-and-7-month-old male, had presented with epilepsy and global developmental delay. Serological testing revealed that he has low serum magnesium. Genetic testing showed that the child has harbored a heterozygous c. 1448delT (p.Val483GlyfsTer29) variant of the CNNM2 gene, which was de novo in origin. The variant has caused substitution of the valine at position 483 to Glycine and formation of a termination codon after 29 amino acids at downstream. As predicted by Swiss-Model online software, the variant may alter the protein structure, resulting in a truncation. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c. 1448del T (p.Val483GlyfsTer29) was predicted as a pathogenic variant (PVS1+ PS2+ PM2_Supporting+ PP4). Conclusion The heterozygous c. 1448delT variant of the CNNM2 gene probably underlay the HSMR in this child. Above finding has enriched the phenotype-genotype specirum of the CNNM2 gene.

    CNNM2基因癫痫低镁血症智力障碍HSMR综合征

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    ERF基因变异所致颅缝早闭患儿1例并文献复习

    王劲王丹曾凌空王石...
    1009-1014页
    查看更多>>摘要：目的 分析1例颅缝早闭新生儿的临床信息与遗传学特征，明确该患儿颅缝早闭的临床表型及遗传学特征。 方法 选取2021年4月因"发现侧脑室增宽1个月余"收治于华中科技大学同济医学院附属武汉儿童医院的1例颅缝早闭患儿作为研究对象，并收集其临床信息。抽取患儿及其父母外周血样品，对患儿进行染色体核型分析，并进行全外显子组测序(WES)及家系Sanger测序验证。依据美国医学遗传学与基因组学学会(ACMG)变异解读标准与指南对基因变异进行致病性评估。文献检索以"ERF基因""颅缝早闭""ERF基因相关颅缝早闭""ERF mutation""craniosynostosis""ERF related craniosynostosis"等为关键词，设定检索年限建库至2021年12月，在美国医学文摘数据库(PubMed)、万方医学网及中国知网(CNKI)数据库中进行检索ERF基因所致颅缝早闭相关文献，并进行遗传学分析。 结果 患儿为1月16日龄女性，头颅X射线摄片检查结果示矢状缝早闭。WES结果提示患儿ERF基因存在变异c.787C>T(p.Q263*)，父母未见该变异。根据ACMG变异标准与指南，变异判定为致病性变异(PVS1+PS2+PM2_Supporting)。按文献检索策略共计检索到63例相关病例，共计64例患儿进行遗传学分析。绝大部分为散发病例，男性患儿居多；多颅缝累及(包括矢状缝、冠状缝、人字缝、额缝中的至少两条缝)占45.45%，单独矢状缝闭合占20.00%。主要临床表现包括眼距增宽、眼球突出、发育迟缓、颧骨发育不良等，部分患儿可能存在Chiari 1型畸形。目前研究结果显示ERF基因变异以剪切变异和缺失变异为主，且大部分先证者或先证者家系变异位点不同。 结论 ERF：c.787C>T(p.Q263*)可能为颅缝早闭患儿致病原因，该变异发现丰富了ERF的表型基因谱。 Objective To analyze the clinical and genetic characteristics of an infant with craniosynostosis. Methods An infant who was admitted to Wuhan Children′s Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology in April 2021 due to widening of the lateral ventricle for over a month was selected as the study subject. Clinical data of the patient was collected. Peripheral blood samples were collected from the infant and her parents for chromosomal karyotyping and whole exome sequencing. Candidate variant was verified by Sanger sequencing and bioinformatic analysis. Relevant literature was retrieved from the PubMed, Wanfang and CNKI databases (up to December 2021) by using key words including ERF gene, craniosynostosis, ERF mutation, craniosynostosis and ERF related craniosynostosis. Results The infant, a 1-month-and-16-day-old female, was found to have sagittal synostosis by cranial X-ray radiography. Genetic testing revealed that she has harbored a heterozygous c. 787C>T (p.Q263*) variant of theERF gene, which was not found in either parent. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted as pathogenic (PVS1+ PS2+ PM2_Supporting). In total 63 relevant cases were retrieved from the database, among which 64 were analyzed by genetic testing. Most of the cases were sporadic and were males. Multiple cranial sutures (including at least two of the sagittal suture, coronal suture, lambdoid suture, and frontal suture) were involved in 45.45% of the cases, and those with sagittal suture closure only have accounted for 20.00%. The main clinical manifestations have included hypertelorism, exophthalmos, development delay, malar dysplasia, etc. Chiari type 1 malformation may present in some patients. Variants of the ERF gene have mainly included splicing and deletional variants, and there was a strong genetic heterogeneity among the infants and their pedigrees. Conclusion The c. 787C>T (p.Q263*) variant of theERF gene probably underlay the craniosynostosis of this infant. Above finding has enriched the phenotype -genotype spectrum of the ERF gene.

    颅缝早闭ERF基因基因变异婴儿

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    临床表现不典型极早发型炎症性肠病28型患儿1例的临床与遗传学分析

    张悦王东康丽丽张欣怡...
    1015-1020页
    查看更多>>摘要：目的 探讨1例临床表现不典型极早发型炎症性肠病(VEO-IBD)28型患儿的临床特征与遗传学病因。 方法 选取2021年11月5日于山东大学附属儿童医院新生儿科就诊的1例临床表现不典型VEO-IBD28型患儿为研究对象。收集患儿临床资料，采集患儿及其父母外周静脉血样，应用高通量测序对患儿进行基因检测，采用Sanger测序进行候选变异家系验证，并进行生物信息学分析。 结果 患儿为50 d龄男性，具有支气管炎、溃疡性口炎、湿疹、大便略稀等临床表现。高通量测序结果提示患儿IL-10RA基因存在c.299T>G(p.V100G)与c.301C>T(p.R101W)复合杂合变异，Sanger测序结果显示患儿父亲IL-10RA基因存在c.299T>G(p.V100G)杂合变异，患儿母亲IL-10RA基因存在c.301C>T(p.R101W)杂合变异。IL-10RA基因c.299T>G与c.301C>T变异在HGMD数据库中均已见报道；经gnomAD、1000 Genomes、ExAC及ESP6500等数据库检索，c.299T>G变异未见收录，c.301C>T变异已见收录且为低频变异；经SIFT、PolyPhen-2及Mutation Taster等在线软件分析，c.299T>G与c.301C>T变异均被预测为可能有害性变异；根据美国医学遗传学与基因组学学会(ACMG)相关指南，c.299T>G与c.301C>T变异均被评级为致病性变异(PS3+PM2_Supporting+PP3)。 结论 IL-10RA基因c.299T>G与c.301C>T变异可能为该VEO-IBD28型患儿的遗传学病因，进一步拓展了IL-10RA基因变异所致VEO-IBD28型患儿表型谱，为该病患儿临床诊断提供参考依据。 Objective To explore the clinical and genetic characteristics of a very early-onset inflammatory bowel disease (VEO-IBD) type 28 child with atypical clinical manifestations. Methods A VEO-IBD type 28 child with atypical clinical manifestation admitted to the Department of Neonatology, Children′s Hospital Affiliated to Shandong University on November 5, 2021 was selected as the study subject. Clinical data of the child was collected. Peripheral venous blood samples of the child and his parents were collected for high-throughput sequencing. Candidate variants were verified by Sanger sequencing and bioinformatic analysis. Results The child, a 50-day old male, had manifested bronchitis, ulcerative stomatitis, eczema and slightly loose stool. High-throughput sequencing revealed that he harbored compound heterozygous variants of the IL-10RA gene, namely c. 299T>G (p.V100G) and c. 301C>T (p.R101W), which were inherited from his father and mother, respectively. Bioinformatic analysis showed that both variants have been recorded in the HGMD database, though the c. 299T>G variant has not been included in the gnomAD, 1000 Genomes, ExAC and ESP6500 databases, while the c. 301C>T variant has a low population frequency. Both variants were predicted to be deleterious by the online software including SIFT, PolyPhen-2 and Mutation Taster. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were predicted to be pathogenic (PS3+ PM2_Supporting+ PP3). Conclusion The c. 299T>G and c. 301C>T variants of theIL-10RA gene probably underlay the VEO-IBD type 28 in this child. Above finding has expanded the phenotypic spectrum of VEO-IBD type 28 due to variants of the IL-10RA gene and provided a reference for the clinical diagnosis of this disease.

    临床表现不典型极早发型炎症性肠病IL-10RA基因高通量测序儿童

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