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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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    新生儿高通量测序基因筛查的前瞻性研究

    庄丹燕王飞丁曙霞郑周数...
    641-647页
    查看更多>>摘要：目的 探索新生儿高通量测序(HTS)基因筛查在新生儿筛查疾病早期诊断中的临床价值。 方法 选取2021年3月至2021年9月于宁波市妇女儿童医院出生的2 060例新生儿为研究对象。对其采用传统串联质谱和荧光免疫分析筛查后，再应用HTS技术对135个筛查疾病相关致病基因的明确致病高频变异位点进行检测，可疑变异位点进行Sanger测序或多重连接探针扩增技术家系验证。 结果 2 060例新生儿中，基因阳性31例，基因携带557例，基因阴性1 472例。31例基因阳性新生儿中，G6PD基因变异5例，遗传性非综合征型耳聋相关基因(GJB2、GJB3、MT-RNR1)变异19例，PAH基因变异2例，GAA基因变异1例，SMN1基因变异1例，MTTL1基因变异2例，GH1基因变异1例。结合基因结果和临床资料确诊脊髓性肌肉萎缩症(SMA)1例，糖原贮积症Ⅱ型1例，耳聋2例，G6PD缺乏症5例，额外诊断患儿母亲SMA 1例。2 060例新生儿经传统串联质谱检测未发现确诊患者；经传统荧光免疫分析筛查发现G6PD缺乏症5例(基因筛查阳性)，甲状腺功能减退症2例(DUOX2基因变异携带者)。宁波地区新生儿基因变异携带率前6位的基因分别为：DUOX2(3.93%)、ATP7B(2.48%)、SLC26A4(2.38%)、GJB2(2.33%)、PAH(2.09%)、SLC22A5(2.09%)。 结论 新生儿基因筛查技术的疾病检测范围广泛，检出率高，与传统筛查联合可显著提高临床筛查效果，有助于患儿的二级预防、家系成员的疾病诊断和变异携带者的遗传咨询。 Objective To assess the value of genetic screening by high-throughput sequencing (HTS) for the early diagnosis of neonatal diseases. Methods A total of 2 060 neonates born at Ningbo Women and Children′s Hospital from March to September 2021 were selected as the study subjects. All neonates had undergone conventional tandem mass spectrometry metabolite analysis and fluorescent immunoassay analysis. HTS was carried out to detect the definite pathogenic variant sites with high-frequency of 135 disease-related genes. Candidate variants were verified by Sanger sequencing or multiplex ligation-dependent probe amplification (MLPA). Results Among the 2 060 newborns, 31 were diagnosed with genetic diseases, 557 were found to be carriers, and 1 472 were negative. Among the 31 neonates, 5 had G6PD, 19 had hereditary non-syndromic deafness due to variants of GJB2, GJB3 and MT-RNR1 genes, 2 had PAH gene variants, 1 had GAA gene variants, 1 had SMN1 gene variants, 2 had MTTL1 gene variants, and 1 had GH1 gene variants. Clinically, 1 child had Spinal muscular atrophy (SMA), 1 had Glycogen storage disease Ⅱ, 2 had congenital deafness, and 5 had G6PD deficiency. One mother was diagnosed with SMA. No patient was detected by conventional tandem mass spectrometry. Conventional fluorescence immunoassay had revealed 5 cases of G6PD deficiency (all positive by genetic screening) and 2 cases of hypothyroidism (identified as carriers). The most common variants identified in this region have involved DUOX2 (3.93%), ATP7B (2.48%), SLC26A4 (2.38%), GJB2 (2.33%), PAH (2.09%) and SLC22A5 genes (2.09%). Conclusion Neonatal genetic screening has a wide range of detection and high detection rate, which can significantly improve the efficacy of newborn screening when combined with conventional screening and facilitate secondary prevention for the affected children, diagnosis of family members and genetic counseling for the carriers.

    新生儿筛查基因检测高通量测序新生儿

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    全外显子组测序对于智力障碍或全面发育迟缓患者的诊断价值

    李阳艳雷冬竹李彩云黄东群...
    648-654页
    查看更多>>摘要：目的 探讨全外显子组测序(WES)对于智力障碍(ID)或全面发育迟缓(GDD)患者的诊断价值。 方法 选取2018年5月至2021年12月于郴州市第一人民医院就诊的134例ID或GDD患者为研究对象。采集患者及其父母的外周血样进行WES检测，对候选变异进行Sanger测序/拷贝数变异测序(CNV-seq)验证和家系来源分析，对候选变异根据美国医学遗传学与基因组学学会(ACMG)变异分类标准进行致病性评估。 结果 在134例患者中，共检出致病性单核苷酸变异(SNV)及小片段插入/缺失(InDel)46例，致病性基因组拷贝数变异(CNV)11例，单亲二倍体(UPD)1例，总体阳性检出率为43.28%(58/134)。46例致病性SNV/InDel共涉及40个基因62个位点，其中最多的是MECP2基因(n＝4)。11例致病性CNV中，10例为缺失变异，1例为重复变异，片段范围为0.76 ~ 15.02 Mb。1例患者在15q11.2q12区存在约15.62 Mb的杂合性丢失(LOH)，结合家系WES数据提示为父源性UPD，结合其临床表型诊断为Angelman综合征。 结论 WES不仅能够高效检出SNV/InDel，对CNV、LOH也有较高的检出率，结合家系数据分析能够准确判断变异的来源，这些优势表明WES对ID或GDD患者的遗传学病因诊断具有重要的价值。 Objective To assess the diagnostic value of whole exome sequencing (WES) for patients with intellectual disability (ID) or global developmental delay (GDD). Methods 134 individuals with ID or GDD who presented at Chenzhou First People′s Hospital between May 2018 and December 2021 were selected as the study subjects. WES was carried out on peripheral blood samples of the patients and their parents, and candidate variants were verified by Sanger sequencing, copy number variation sequencing(CNV-seq) and co-segregation analysis. The pathogenicity of the variants was predicted based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). Results A total of 46 pathogenic single nucleotide variants (SNVs) and small insertion/deletion (InDel) variants, 11 pathogenic genomic copy number variants (CNVs), and 1 uniparental diploidy (UPD) were detected, which yielded an overall detection rate of 43.28% (58/134). The 46 pathogenic SNV/InDel have involved 62 mutation sites in 40 genes, among which MECP2 was the most frequent (n=4). The 11 pathogenic CNVs have included 10 deletions and 1 duplication, which have ranged from 0.76 to 15.02 Mb. A loss of heterozygosity (LOH) region of approximately 15.62 Mb was detected in 15q11.2q12 region in a patient, which was validated as paternal UPD based on the result of trio-WES. The patient was ultimately diagnosed as Angelman syndrome. Conclusion WES can detect not only SNV/InDel, but also CNV and LOH. By integrating family data, WES can accurately determine the origin of the variants and provide a useful tool for uncovering the genetic etiology of patients with ID or GDD.

    全外显子组测序拷贝数变异测序智力障碍全面发育迟缓诊断价值

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    东莞地区35 145例育龄人群脊髓性肌萎缩症携带者筛查的结果分析

    赵颖娄季武付有晴戴韵诗...
    655-660页
    查看更多>>摘要：目的 对东莞地区育龄人群进行脊髓性肌萎缩症(SMA)的携带者筛查，探讨本地区人群SMN1基因缺失的携带率。 方法 选取2020年3月至2022年8月在东莞市妇幼保健院接受SMN1基因筛查的表型正常的育龄期男女为研究对象。采用实时荧光定量PCR(qPCR)技术对受试者SMN1基因的第7/8外显子(E7/E8)进行缺失检测，并对夫妻双方均为携带者的家系应用多重连接探针扩增(MLPA)进行产前诊断。 结果 在35 145例筛查者中，SMN1基因第7外显子缺失的携带者635例(E7/E8杂合缺失586例，E7杂合缺失伴E8纯合缺失2例，单纯E7杂合缺失47例)，携带率为1.81%(635/35 145)。男性携带率为1.59%(29/1 821)，女性携带率为1.82%(606/33 324)，2组差异无统计学意义(χ2 ＝ 0.497，P＝0.481)。1例29岁女性为SMN1基因E7/E8纯合缺失，MLPA验证其SMN1基因型为[0∶ 4]。其家系中有3名[0 ∶ 4]基因型成员均未见相关的临床症状。共11对携带者夫妻进行产前诊断，1例[0 ∶ 4]基因型胎儿被终止妊娠。 结论 本研究首次确定了东莞地区SMA的人群携带率并对高风险夫妇提供了产前诊断，其结果可为SMA的遗传咨询、产前诊断提供参考，对SMA的出生缺陷防控具有重要的意义。 Objective To carry out carrier screening for Spinal muscular atrophy (SMA) in reproductive-aged individuals from Dongguan region and determine the carrier frequency of SMN1 gene mutations. Methods Reproductive-aged individuals who underwent SMN1 genetic screening at the Dongguan Maternal and Child Health Care Hospital from March 2020 to August 2022 were selected as the study subjects. Deletions of exon 7 and 8 (E7/E8) of the SMN1 gene were detected by real-time fluorescence quantitative PCR (qPCR), and prenatal diagnosis was provided for carrier couples by multiple ligation-dependent probe amplification (MLPA). Results Among the 35 145 subjects, 635 were found to be carriers of SMN1 E7 deletion (586 with heterozygous E7/E8 deletion, 2 with heterozygous deletion E7 and homozygous E8 deletion, and 47 with sole heterozygous E7 deletion). The carrier frequency was 1.81% (635/35 145), with 1.59% (29/1 821) in males and 1.82% (606/33 324) in females. There was no significant difference between the two genders (χ2 = 0.497, P=0.481). A 29-year-old woman was found to harbor homozygous deletion of SMN1 E7/E8, and was verified to have a SMN1∶SMN2 ratio of [0∶4], none of her three family members with a [0∶4] genotype had clinical symptoms. Eleven carrier couples had accepted prenatal diagnosis, and one fetus was found to have a [0∶4] genotype, and the pregnancy was terminated. Conclusion This study has determined the SMA carrier frequency in Dongguan region for the first time and provided prenatal diagnosis for carrier couples. The data can provide a reference for genetic counseling and prenatal diagnosis, which has important clinical implications for the prevention and control of birth defects associated with SMA.

    脊髓性肌萎缩症SMN1基因实时荧光定量PCR多重连接探针扩增携带者筛查成人

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    Waardenburg综合征4个家系的临床表型与基因变异分析

    王璐璐毛璐许红恩孙淑萍...
    661-667页
    查看更多>>摘要：目的 探讨4例Waardenburg综合征(WS)先证者的致病原因。 方法 选取2021年7月至2022年3月就诊于郑州大学第一附属医院的4例WS先证者及其家系为研究对象。先证者1为2岁11月龄女性患儿，于2021年11月3日因"言语不清2+年"就诊；先证者2为10岁女性患儿，于2021年7月13日因"双耳听力差8年"就诊；先证者3为28岁男性患者，于2022年3月23日因"右耳听力下降10+年"就诊；先证者4为2岁龄男性患儿，于2022年3月9日因"左耳听力差1年"就诊。收集先证者及其家系成员的病史资料，并进行听力学检查和颞部CT检查。提取先证者及其家系成员血样基因组DNA进行全外显子组测序，并进行Sanger测序验证。 结果 先证者1表现为双耳极重度感音神经性耳聋、双眼蓝色虹膜及内眦外移，存在父源PAX3：c.667C>T(p.Arg223Ter)无义杂合变异。根据美国医学遗传学与基因组学学会(ACMG)的变异评级指南，该变异评级为致病性变异(PVS1+PM2_Supporting+PP4)，先证者1确诊为WSⅠ型。先证者2表现为右耳中度感音神经性耳聋、左耳极重度感音神经性耳聋、双眼蓝色虹膜及内耳发育畸形，存在SOX10：c.1018_1022del(p.Val340SerfsTer60)移码杂合变异，先证者2的父母此位点为野生型，考虑为新发变异。根据ACMG的变异评级指南，SOX10：c.1018_1022del变异评级为致病性变异(PVS1+PM2_Supporting+PP4+PM6)，先证者2确诊为WSⅡ型。先证者3表现为右耳极重度感音神经性耳聋、左耳听力未见异常。存在SOX10：c.23delC(p.Ser8TrpfsTer5)移码杂合变异，变异来源未知。根据ACMG的变异评级指南，SOX10：c.23delC变异评级为致病性变异(PVS1+PM2_Supporting+PP4)，先证者3确诊为WSⅡ型。先证者4表现为左耳极重度感音神经性耳聋、右耳听力未见异常，存在母源性MITF：c.7G>T(p.Glu3Ter)无义杂合变异。根据ACMG的变异评级指南，MITF：c.7G>T变异评级为致病性变异(PVS1+PM2_Supporting+PP4)，先证者4确诊为WSⅡ型。 结论 本研究通过基因检测确诊了4例WS型患者，能够为WS家系提供了分子病因学诊断和遗传咨询，进一步增强了临床医师对WS的认识。 Objective To explore the genetic basis for four Chinese pedigrees affected with Waardenburg syndrome (WS). Methods Four WS probands and their pedigree members who had presented at the First Affiliated Hospital of Zhengzhou University between July 2021 and March 2022 were selected as the study subjects. Proband 1, a 2-year-and-11-month female, had blurred speech for over 2 years. Proband 2, a 10-year-old female, had bilateral hearing loss for 8 years. Proband 3, a 28-year-old male, had right side hearing loss for over 10 years. Proband 4, a 2-year-old male, had left side hearing loss for one year. Clinical data of the four probands and their pedigree members were collected, and auxiliary examinations were carried out. Genomic DNA was extracted from peripheral blood samples and subjected to whole exome sequencing. Candidate variants were verified by Sanger sequencing. Results Proband 1, with profound bilateral sensorineural hearing loss, blue iris and dystopia canthorum, was found to have harbored a heterozygous c. 667C>T (p.Arg223Ter) nonsense variant of thePAX3 gene, which was inherited from her father. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as pathogenic (PVS1+ PM2_Supporting+ PP4), and the proband was diagnosed with WS type Ⅰ. Proband 2, with moderate sensorineural hearing loss on the right side and severe sensorineural hearing loss on the left side, has harbored a heterozygous frameshifting c. 1018_1022del (p.Val340SerfsTer60) variant of the SOX10 gene. Neither of her parents has harbored the same variant. Based on the ACMG guidelines, it was classified as pathogenic (PVS1+ PM2_Supporting+ PP4+ PM6), and the proband was diagnosed with WS type Ⅱ. Proband 3, with profound sensorineural hearing loss on the right side, has harbored a heterozygous c. 23delC (p.Ser8TrpfsTer5) frameshifting variant of the SOX10 gene. Based on the ACMG guidelines, it was classified as pathogenic (PVS1+ PM2_Supporting+ PP4), and the proband was diagnosed with WS type Ⅱ. Proband 4, with profound sensorineural hearing loss on the left side, has harbored a heterozygous c. 7G>T (p.Glu3Ter) nonsense variant of theMITF gene which was inherited from his mother. Based on the ACMG guidelines, the variant was classified as pathogenic (PVS1+ PM2_Supporting+ PP4), and the proband was diagnosed with WS type Ⅱ. Conclusion By genetic testing, the four probands were all diagnosed with WS. Above finding has facilitated molecular diagnosis and genetic counseling for their pedigrees.

    Waardenburg综合征新发变异PAX3基因SOX10基因MITF基因家系

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    ATP7A基因变异所致Menkes病患儿3例的临床及遗传学分析

    王泽兵陈巧媚王优刘玲...
    668-673页
    查看更多>>摘要：目的 探讨3例ATP7A基因变异所致Menkes病患儿的临床特征与遗传学病因。 方法 选取2020年1月至2022年7月于广东医科大学附属医院儿童医学中心就诊的3例Menkes病患儿作为研究对象。收集3例患儿的临床资料，采集3例患儿及其父母和患儿1姐姐的外周血样，对患儿进行全外显子组测序(WES)，用Sanger测序与拷贝数变异测序(CNV-seq)对候选变异进行家系验证，并对其进行生物信息学分析。 结果 患儿1为1岁4月龄的男性，患儿2和3为1岁10月龄的同卵男性双胎。3例患儿均表现为发育落后及癫痫发作。WES检测提示患儿1携带ATP7A基因c.3294+1G>A杂合变异，经Sanger测序验证其父母与姐姐均未携带该变异，提示为新发变异；患儿2和3携带c.77266650_77267178del拷贝数缺失变异，经CNV-seq验证，其母亲携带相同变异，父亲未见该变异。经检索HGMD、OMIM及ClinVar等数据库，ATP7A基因c.3294+1G>A变异为已知致病变异；在1000 Genomes、ESP、ExAC及gnomAD等数据库中未见正常人群的携带频率；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。c.77266650_77267178del拷贝数缺失变异涉及ATP7A基因的第8~9外显子，ClinGen在线系统对该变异的评分为1.8分，考虑为致病性。 结论 ATP7A基因c.3294+1G>A变异以及c.77266650_77267178del拷贝数缺失变异分别为患儿1、患儿2和3的遗传学病因。上述发现进一步丰富了Menkes病的变异谱，为患儿的临床诊断和遗传咨询提供了依据。 Objective To explore the clinical characteristics and genetic etiology of three children with Menkes disease. Methods Three children who had presented at the Children′s Medical Center, the Affiliated Hospital of Guangdong Medical University from January 2020 to July 2022 were selected as the study subjects. Clinical data of the children were reviewed. Genomic DNA was extracted from peripheral blood samples of the children, their parents and sister of child 1. Whole exome sequencing (WES) was carried out. Candidate variants were verified by Sanger sequencing, copy number variation sequencing (CNV-seq), and bioinformatic analysis. Results Child 1 was a 1-year-and-4-month male, and children 2 and 3 were monozygotic twin males aged 1-year-and-10-month. The clinical manifestations of the three children have included developmental delay and seizures. WES showed that child 1 has harbored a c. 3294+ 1G>A variant of theATP7A gene. Sanger sequencing confirmed that his parents and sister did not carry the same variant, suggesting that it was de novo. Children 2 and 3 had carried a c. 77266650_77267178del copy number variation. CNV-seq results showed that their mother has carried the same variant. By searching the HGMD, OMIM and ClinVar databases, the c. 3294+ 1G>A was known to be pathogenic. No carrier frequency has been recorded in the 1000 Genomes, ESP, ExAC and gnomAD databases. 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), theATP7A gene c. 3294+ 1G>A variant was predicted to be pathogenic. The c. 77266650_77267178del variant has involved exons 8 to 9 of theATP7A gene. ClinGen online system score for it was 1.8, which was also considered to be pathogenic. Conclusion The c. 3294+ 1G>A and c. 77266650_ 77267178del variants of theATP7A gene probably underlay the Menkes disease in the three children. Above finding has enriched the mutational spectrum of Menkes disease and provided a basis for clinical diagnosis and genetic counseling.

    Menkes病ATP7A基因癫痫发作发育落后儿童

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    基于单细胞RNA测序的人类宫腔中度粘连组织中独特的细胞分子学特征研究

    刘运华吴志军徐州栋何佩清...
    674-679页
    查看更多>>摘要：目的 构建人类宫腔粘连(IUA)组织的细胞景观及其分子生物学特征，以便更好地了解其免疫微环境，为临床治疗提供新的思路。 方法 选取2022年2月至2022年4月在东莞市妇幼保健院接受宫腔镜治疗的4例IUA患者为研究对象。利用宫腔镜采集IUA组织，并根据患者的病史、月经史及IUA状态等评分和分级，样本采集后立即送检。严格按照单细胞RNA测序流程进行文库构建、测序、数据比对和基因表达矩阵构建，之后进行细胞分群UMAP降维分析和基于细胞类型的差异基因分析。 结果 收集到4例分级为中度的IUA组织样本，共获得27 511个细胞转录组，分配到6个细胞谱系，分别为T细胞、单核吞噬细胞、上皮细胞、成纤维细胞、内皮细胞和红细胞。与文献报道的正常子宫组织细胞相比，本研究的4例样本具有不同的细胞分布，IUA0202204号样本中单核吞噬细胞与T细胞的占比明显偏高，提示存在较强的细胞免疫反应。 结论 描述了中度IUA组织的细胞多样性和异质性，以及各细胞亚群的分子学特征，为进一步研究IUA的发病机制与患者的异质性提供了线索。 Objective To depict the cell landscape and molecular biological characteristics of human intrauterine adhesion (IUA) so as to better understand its immune microenvironment and provide new inspirations for clinical treatment. Methods Four patients with IUA who underwent hysteroscopic treatment at Dongguan Maternal and Child Health Care Hospital from February 2022 to April 2022 were selected as the study subjects. Hysteroscopy was used to collect the tissues of IUA, which were graded based on the patient’s medical history, menstrual history and status of IUA. Library construction, sequencing, single cell data comparison and gene expression matrix construction were carried out in strict accordance with the single cell RNA sequencing process. Thereafter, the UMAP dimension reduction analysis of cell population and genetic analysis were carried out based on the cell types. Results A total of 27 511 cell transcripts were obtained from four moderately graded IUA tissue samples and assigned to six cell lineages including T cells, mononuclear phagocytes, epithelial cells, fibroblasts, endothelial cells and erythrocytes. Compared with normal uterine tissue cells, the four samples showed different cell distribution, and the proportions of mononuclear phagocytes and T cells in sample IUA0202204 were significantly increased, suggesting a strong cellular immune response. Conclusion The cell diversity and heterogeneity of moderate IUA tissues have been described. Each cell subgroup has unique molecular characteristics, which may provide new clues for further study of the pathogenesis of IUA and heterogeneity among the patients.

    单细胞RNA测序宫腔粘连异质性单核吞噬细胞成纤维细胞

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    母源低比例 TCF4基因嵌合变异所致Pitt-Hopkins综合征患儿1例的遗传学分析

    唐娇令军鹤张钏郝胜菊...
    680-685页
    查看更多>>摘要：目的 探讨l例Pitt-Hopkins综合征患儿的遗传学病因。 方法 选取2021年2月24日就诊于甘肃省妇幼保健院医学遗传中心遗传门诊的1例Pitt-Hopkins综合征患儿及其一级亲属为研究对象。收集先证者的临床资料，提取先证者及其父母的外周血样基因组DNA进行家系全外显子组测序(trio-WES)，针对候选变异进行Sanger测序验证，并对先证者进行染色体核型分析，对其再孕母亲进行超高深度测序和羊水产前诊断。 结果 先证者表现为特殊面容、通贯掌、精神发育迟滞及智力异常。基因检测提示其携带TCF4基因c.1762C>T(p.Arg588Cys)杂合变异，其父母均为野生型。该变异既往未见报道，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。超高深度测序提示先证者母亲该位点的变异率为2.63%，提示存在低比例嵌合。羊水产前诊断结果提示胎儿未携带同样的致病变异。 结论 先证者TCF4基因c.1762C>T杂合变异可能是其遗传学病因，其致病变异可能源于母亲的低比例嵌合变异。 Objective To explore the genetic etiology of a child with Pitt-Hopkins syndrome. Methods A child who had presented at the Medical Genetics Center of Gansu Provincial Maternal and Child Health Care Hospital on February 24, 2021 and his parents were selected as the study subjects. Clinical data of the child was collected. Genomic DNA was extracted from peripheral blood samples of the child and his parents and subjected to trio-whole exome sequencing (trio-WES). Candidate variant was verified by Sanger sequencing. Karyotype analysis was also carried out for the child, and her mother was subjected to ultra-deep sequencing and prenatal diagnosis upon her subsequent pregnancy. Results The clinical manifestations of the proband included facial dysmorphism, Simian crease, and mental retardation. Genetic testing revealed that he proband has carried a heterozygous c. 1762C>T (p.Arg588Cys) variant of theTCF4 gene, for which both parents had a wild-type. The variant was unreported previously and was rated as likely pathogenic based on the guidelines of the American College of Medical Genetics and Genomics (ACMG). Ultra-deep sequencing indicated that the variant has a proportion of 2.63% in the mother, suggesting the presence of low percentage mosaicism. Prenatal diagnosis of amniotic fluid sample suggested that the fetus did not carry the same variant. Conclusion The heterozygous c. 1762C>T variant of theTCF4 gene probably underlay the disease in this child and has derived from the low percentage mosaicism in his mother.

    全外显子组测序TCF4基因Pitt-Hopkins综合征嵌合变异儿童

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    CHRNG基因新发变异致多发性翼状胬肉综合征1例的遗传学分析

    陈亦儒农恬颖石伟哲李建贵...
    686-690页
    查看更多>>摘要：目的 探讨1例多发性翼状胬肉综合征(MPS)患儿的临床特征及遗传学病因。 方法 选取2020年8月19日于广州市妇女儿童医疗中心骨科就诊的1例MPS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，对患儿进行全外显子组测序(WES)，用Sanger测序对候选变异进行家系验证，并进行生物信息学分析。 结果 患儿为女性，11岁，因"发现脊柱侧弯8年，加重伴双肩不等高1年"就诊。WES检测结果提示其携带CHRNG基因c.55+1G>C纯合剪接变异，Sanger测序证实其父母均携带CHRNG基因c.55+1G>C杂合剪接变异。生物信息学分析：CHRNG基因c.55+1G>C变异在CNKI、万方数据知识服务平台及HGMG等数据库中均未见收录。经Multain在线软件分析，该位点所编码的氨基酸在不同物种中高度保守。经CRYP-SKIP在线软件预测，该变异导致第1外显子潜在剪接位点激活与跳跃的概率分别为0.30与0.70。确诊患儿罹患MPS。 结论 CHRNG基因c.55+1G>C变异可能是本研究MPS患儿的遗传学病因。 Objective To explore the clinical characteristics and genetic etiology of a child with multiple pterygium syndrome (MPS). Methods A child with MPS who was treated at the Orthopedics Department of Guangzhou Women and Children′s Medical Center Affiliated to Guangzhou Medical University on August 19, 2020 was selected as the study subject. Clinical data of the child was collected. Peripheral blood samples of the child and her parents were also collected. Whole exome sequencing (WES) was carried out for the child. Candidate variant was validated by Sanger sequencing of her parents and bioinformatic analysis. Results The child, an 11-year-old female, had a complain of "scoliosis found 8 years before and aggravated with unequal shoulder height for 1 year". WES results revealed that she has carried a homozygous c. 55+ 1G>C splice variant of the CHRNG gene, for which both of her parents were heterozygous carriers. By bioinformatic analysis, the c. 55+ 1G>C variant has not been recorded by the CNKI, Wanfang data knowledge service platform and HGMG databases. Analysis with Multain online software suggested that the amino acid encoded by this site is highly conserved among various species. As predicted with the CRYP-SKIP online software, the probability of activation and skipping of the potential splice site in exon 1 caused by this variant is 0.30 and 0.70, respectively. The child was diagnosed with MPS. Conclusion The CHRNG gene c. 55+ 1G>C variant probably underlay the MPS in this patient.

    多发性翼状胬肉综合征CHRNG基因新变异儿童

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    先天性心脏病伴全面发育迟缓患儿1例的 NONO基因变异分析

    雷宇清彭小燕王心睿曹华...
    691-695页
    查看更多>>摘要：目的 探讨1例先天性心脏病(CHD)伴全面发育迟缓(GDD)患儿的遗传学病因。 方法 选取2022年4月27日于福建省儿童医院心脏外科就诊的1例CHD伴GDD患儿为研究对象。收集患儿的临床资料，采集患儿的脐带血样及其父母的外周静脉血样，用全外显子组测序(WES)对患儿进行检测，对候选变异进行Sanger测序家系验证，并分析其致病性。 结果 患儿为男性，3岁3个月，具有心脏异常及发育迟缓等表现。WES检测结果提示其NONO基因存在c.457C>T(p.Arg153*)无义变异，Sanger测序证实其父母均未携带相同的变异。该变异已被在线人类孟德尔遗传(OMIM)、美国国家生物技术信息中心临床突变数据库(ClinVar)及人类基因突变数据库(HGMD)收录；而未被国际千人基因组计划数据库(1000 Genomes)、单核苷酸多态性数据库(dbSNP)和基因组聚合数据库(gnomAD)等正常人群数据库收录。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。 结论 NONO基因c.457C>T(p.Arg153*)变异可能是本研究CHD伴全面发育迟缓患儿的遗传学病因。上述发现丰富了NONO基因c.457C>T(p.Arg153*)变异的表型谱，为患儿的临床诊断与家系遗传咨询提供了依据。 Objective To explore the genetic basis for a child with congenital heart disease (CHD) and global developmental delay (GDD). Methods A child who was hospitalized at the Department of Cardiac Surgery of Fujian Children′s Hospital on April 27, 2022 was selected as the study subject. Clinical data of the child was collected. Umbilical cord blood sample of the child and peripheral blood samples of 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 3-year-and-3-month-old boy, had manifested cardiac abnormalities and developmental delay. WES revealed that he had harbored a nonsense variant of c. 457C>T(p.Arg153*) in theNONO gene. Sanger sequencing showed that neither of his parents has carried the same variant. The variant has been recorded by the OMIM, ClinVar and HGMD databases, but not in the normal population databases of 1000 Genomes, dbSNP and gnomAD. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), it was rated as a pathogenic variant. Conclusion The c. 457C>T(p.Arg153*) variant of theNONO gene probably underlay the CHD and GDD in this child. Above finding has expanded the phenotypic spectrum of the NONO gene and provided a reference for the clinical diagnosis and genetic counseling for this family.

    先天性心脏病全面发育迟缓NONO基因全外显子组测序

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    常染色体显性遗传性智力障碍51型患儿1例的临床与遗传学分析

    唐玉琳李小晶吴汶霖石真...
    696-700页
    查看更多>>摘要：目的 探讨1例常染色体显性遗传性智力障碍51型(MRD51)患儿的临床特征与遗传学病因。 方法 选取2022年3月4日于广州市妇女儿童医疗中心就诊的1例MRD51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。 结果 患儿为女性，5岁3个月，具有孤独症谱系障碍(ASD)、智力障碍(MR)、反复热性惊厥、特殊面容等临床表现。WES检测结果提示，患儿KMT5B基因存在c.142G>T (p.Glu48Ter)杂合变异，Sanger测序结果显示患儿父母均未携带该变异，提示为新发变异。生物信息学分析：KMT5B基因c.142G>T (p.Glu48Ter)变异在ClinVar、OMIM、HGMD、ESP、ExAC及1000 Genomes等数据库中，均未见报道；采取Mutation Taster、GERP++及CADD等在线软件对该变异有害性分析结果显示，均提示为致病性变异；采取SWISS-MODEL在线软件预测显示，该变异对KMT5B蛋白结构产生显著影响；根据美国医学遗传学与基因组学学会(ACMG)制定的相关指南，该变异被评级为致病性变异。 结论 KMT5B基因c.142G>T (p.Glu48Ter)变异可能为本研究MRD51患儿的遗传学病因，进一步拓展了KMT5B基因变异谱，为该病患儿临床诊断与遗传咨询提供参考依据。 Objective To explore the clinical characteristics and genetic basis of a child with Mental retardation autosomal dominant 51 (MRD51). Methods A child with MRD51 who was hospitalized at Guangzhou Women and Children′s Medical Center on March 4, 2022 was selected as the study subject. Clinical data of the child was collected. Peripheral blood samples of the child and her parents were collected and subjected to whole exome sequencing (WES). Candidate variants were verified by Sanger sequencing and bioinformatic analysis. Results The child, a 5-year-and-3-month-old girl, had manifested autism spectrum disorder (ASD), mental retardation (MR), recurrent febrile convulsions and facial dysmorphism. WES revealed that she has harbored a novel heterozygous variant of c. 142G>T (p.Glu48Ter) in theKMT5B gene. Sanger sequencing confirmed that neither of her parents has carried the same variant. The variant has not been recorded in the ClinVar, OMIM and HGMD, ESP, ExAC and 1000 Genomes databases. Analysis with online software including Mutation Taster, GERP+ + and CADD indicated it to be pathogenic. Prediction with SWISS-MODEL online software suggested that the variant may have a significant impact on the structure of KMT5B protein. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted to be pathogenic. Conclusion The c. 142G>T (p.Glu48Ter) variant of theKMT5B gene probably underlay the MRD51 in this child. Above finding has expanded the spectrum of KMT5B gene mutations and provided a reference for clinical diagnosis and genetic counseling for this family.

    KMT5B基因孤独症谱系障碍智力障碍惊厥,发热性

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