首页期刊导航|中华医学遗传学杂志
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。
正式出版
收录年代

    21羟化酶缺陷导致的先天性肾上腺皮质增生症的实验室诊断共识

    孙昱邬玲仟叶蕾邱文娟...
    769-780页
    查看更多>>摘要：21羟化酶缺陷(21-OHD)是由于编码参与糖皮质激素和盐皮质激素合成的细胞色素P450氧化酶(P450C21)的CYP21A2基因缺陷导致的遗传病，是先天性肾上腺皮质增生症最常见的类型，其确诊需结合临床表现、实验室生化指标和分子遗传学检测的结果综合判断。由于CYP21A2结构复杂，对其进行基因诊断需采用特殊的检测方法以排除假基因的干扰。近年来，21-OHD的类固醇激素谱生化检测技术和三代测序分子诊断技术逐渐得到推广。为进一步规范21-OHD的实验室诊断，由中华医学会儿科分会罕见病学组、中国医师协会医学遗传医师分会、中国妇幼保健协会分子遗传专委会及上海市医学会分子诊断专科分会组织专家进行讨论，并参考国内外的最新研究进展和共识指南，就21-OHD的实验室诊断规范制定本共识。 21 hydroxylase deficiency (21-OHD), the most common form of congenital adrenal hyperplasia, is caused by defects in CYP21A2 gene, which encodes the cytochrome P450 oxidase (P450C21) involved in glucocorticoid and mineralocorticoid synthesis. The diagnosis of 21-OHD is based on the comprehensive evaluation of clinical manifestation, biochemical alteration and molecular genetics results. Due to the complex structure of CYP21A2, special techniques are required to perform delicate analysis to avoid the interference of its pseudogene. Recently, the state-of-the-art diagnostic methods were applied to the clinic gradually, including the steroid hormone profiling and third generation sequencing. To standardize the laboratory diagnosis of 21-OHD, this consensus was drafted on the basis of the extensive knowledge, the updated progress and the published consensuses and guidelines worldwide by expert discussion organized by Rare Diseases Group of Pediatric Branch of Chinese Medical Association, Medical Genetics Branch of Chinese Medical Doctor Association, Birth Defect Prevention and Molecular Genetics Branch of China Maternal and Child Health Association. and Molecular Diagnosis Branch of Shanghai Medical Association.

    21羟化酶缺陷先天性肾上腺皮质增生症CYP21A2基因共识

      原文链接:
    • 万方数据

    FBN1基因变异患者4例的临床表现及遗传学分析

    刘鑫杨媚谢寒冰赵倩颖...
    781-786页
    查看更多>>摘要：目的 探讨4例疑似马凡综合征(MFS)患者的遗传学病因。 方法 选取2019年9月12日至2021年3月27日就诊于四川大学华西第二医院的4例疑似MFS的男性患者及其家系成员作为研究对象。采集患者及其亲属的外周静脉血样，提取基因组DNA，对其进行家系全外显子组测序，并用Sanger测序对候选变异进行验证。根据美国医学遗传学与基因组学学会(ACMG)变异相关指南判定变异的致病性。 结果 全外显子组测序结果提示4例患者FBN1基因分别存在第5外显子c.430_433del(p.His144fs)缺失变异、第6外显子c.493C>T(p.Arg165*)无义变异、第44外显子c.5304_5306del(p.Asp1768del)缺失变异以及第42外显子c.5165C>G(p.Ser1722Cys)错义变异。根据ACMG变异相关指南，c.430_433del和c.493C>T变异评级为致病性变异(PVS1+PM2_Supporting+PP4；PVS1+PS1+PS2+PM2_Supporting+PP4)。c.5304_5306del和c.5165C>G变异评级为可能致病性变异(PS2+PM2_Supporting+PM4+PP4；PS2_Moderate+PS1+PM1+PM2_Supporting)。 结论 FBN1基因的c.430_433del、c.5304_5306del既往未见报道，上述结果丰富了MFS的基因变异谱，为患者的遗传咨询和产前诊断提供了依据。 Objective To explore the genetic basis for four patients suspected for Marfan syndrome (MFS). Methods Four male patients with suspected MFS and their family members who were treated at West China Second Hospital of Sichuan University from September 12, 2019 to March 27, 2021 were selected as the study subjects. Peripheral venous blood samples were collected from the patients and their parents or other pedigree members for the extraction of genomic DNA. Whole exome sequencing was carried out, and candidate variants were validated by Sanger sequencing. The pathogenicity of the variants was determined based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). Results Genetic testing revealed that all four patients had harbored variants of the FBN1 gene, including c. 430_433del (p.His144fs) deletional variant in exon 5, c. 493C>T (p.Arg165*) nonsense variant in exon 6, c. 5304_5306del (p.Asp1768del) deletional variant in exon 44 and c. 5165C>G (p.Ser1722Cys) missense variant in exon 42. According to the ACMG guidelines, the c. 430_433del and c. 493C>T were classified as pathogenic variants (PVS1+ PM2_Supporting+ PP4 PVS1+ PS1+ PS2+ PM2_Supporting+ PP4). c. 5304_5306del and c. 5165C>G were classified as likely pathogenic variants (PS2+ PM2_Supporting+ PM4+ PP4 PS2_Moderate+ PS1+ PM1+ PM2_Supporting). Conclusion The c. 430_433del and c. 5304_5306del variants of the FBN1 gene identified in this study were unreported previously. Above results have enriched the variation spectrum of the FBN1 gene and provided a basis for genetic counseling and prenatal diagnosis of patients with MFS and acromicric dysplasia.

    FBN1基因杂合变异全外显子组测序马凡综合征肢端发育不良

      原文链接:
    • 万方数据

    中链酰基辅酶A脱氢酶缺乏症4例患儿的临床特点及 ACADM基因变异分析

    肖梦君谢振华刘菁李娴...
    787-794页
    查看更多>>摘要：目的 探讨4例中链酰基辅酶A脱氢酶缺乏症(MCADD)患儿的临床及遗传学特点。 方法 对2019年8月至2021年8月就诊于郑州大学附属儿童医院、经血氨基酸及酯酰肉碱谱检测和全外显子组测序确诊的4例MCADD患儿进行分析。 结果 4例患儿均已发病，血氨基酸及酯酰肉碱谱检测辛酰肉碱(C8)浓度均显著升高，主要临床表现为精神反应差3例、间断腹泻伴腹痛1例、呕吐1例、转氨酶升高3例、代谢性酸中毒2例。基因测序共发现5处变异，包括3处错义变异、1处移码变异以及1处剪接变异，其中c.341A>G(p.Y114C)既往未见报道。 结论 MCADD临床异质性明显，全外显子组测序可协助诊断。了解该病的临床症状及基因变异特点，有助于尽早诊断和治疗。 Objective To explore the clinical and genetic characteristics of four patients with medium-chain acyl-CoA dehydrogenase deficiency (MCADD). Methods Four children who had presented at the Children′s Hospital Affiliated to Zhengzhou University between August 2019 and August 2021 were selected as the study subjects. Clinical data of the children were collected. The children were subjected to whole exome sequencing (WES). Results All of the four children were diagnosed with MCADD. Blood amino acid and ester acyl carnitine spectrum test showed that the concentration of octanoyl carnitine (C8) was significantly increased. The main clinical manifestations included poor mental response (3 cases), intermittent diarrhea with abdominal pain (1 case), vomiting (1 case), increased transaminase (3 cases), and metabolic acidosis (2 cases). Five variants were identified by genetic testing, among which c. 341A>G(p.Y114C) was unreported previously. Three were missense variants, one was frameshift variant and one was splicing variant. Conclusion The clinical heterogeneity of MCADD is obvious, and the severity of the disease may vary. WES can assist with the diagnosis. Delineation of the clinical symptoms and genetic characteristics of the disease can facilitate early diagnosis and treatment of the disease.

    中链酰基辅酶A脱氢酶缺乏症遗传代谢性疾病ACADM基因

      原文链接:
    • 万方数据

    3M综合征患儿4例的临床特点及文献复习

    徐宁安刘康香钟燕李岭...
    795-801页
    查看更多>>摘要：目的 分析3M综合征的临床特征及用生长激素治疗的效果。 方法 回顾性分析2014年1月至2022年2月在湖南省儿童医院经全外显子组测序确诊的3M综合征患儿的临床表现、基因测序结果及生长激素治疗情况，并系统回顾相关文献。 结果 4例患儿均存在严重的生长落后、特殊面容和骨骼异常。基因检测提示2例患儿存在CUL7基因纯合变异，分别为c.4717C>T(p.R1573*)和c.967_993delins CAGCTGG(p.S323Qfs*33)，2例患儿携带OBSL1基因杂合变异，分别为c.1118G>A(p.W373*)、c.458dupG(p.L154Pfs*1002)和c.690dupC(p.E231Rfs*23)，其中c.967_993delinsCAGCTGG和c.1118G>A既往未见报道。文献复习共纳入18例中国3M综合征患儿，其中CUL7基因变异者11例(11/18，61.1%)，OBSL1基因变异者7例(7/18，38.9%)，未发现CDCC8基因变异者。患儿的男女比例为1∶ 1，主要临床表现与文献报道一致。4例患者接受了生长激素治疗，其中3人治疗后有明显生长加速，均未发生不良反应。 结论 3M综合征具有典型的外貌特征，同时伴有显著的身材矮小。临床对于身高在-3s以下且伴有特殊面容的儿童应进行基因检测。生长激素治疗对3M综合征患者的远期有效性尚待进一步的观察。 Objective To analyze the clinical features of 3M syndrome and effect of growth hormone therapy. Methods Clinical data of four children diagnosed with 3M syndrome by whole exome sequencing at Hunan Children′s Hospital from January 2014 to February 2022 were retrospectively analyzed, which included clinical manifestation, results of genetic testing and recombinant human growth hormone (rhGH) therapy. A literature review was also carried our for Chinese patients with 3M syndrome. Results The clinical manifestations of the 4 patients included severe growth retardation, facial dysmorphism and skeletal malformations. Two patients were found to harbor homozygous variants of CUL7 gene, namely c. 4717C>T (p.R1573*) and c. 967_993delinsCAGCTGG (p.S323Qfs*33). Two patients were found to harbor 3 heterozygous variants of theOBSL1 gene including c. 1118G>A (p.W373*), c. 458dupG (p.L154Pfs*1002) and c. 690dupC (p.E231Rfs*23), among which c. 967_993delinsCAGCTGG and c. 1118G>A were unreported previously. Eighteen Chinese patients with 3M syndrome were identified through the literature review, including 11 cases (11/18, 61.1%) carryingCUL7 gene variants and 7 cases (7/18, 38.9%) carrying OBSL1 gene variants. The main clinical manifestations were in keeping with previously reported. Four patients were treated with growth hormone, 3 showed obvious growth acceleration, and no adverse reaction was noted. Conclusion 3M syndrome has a typical appearance and obvious short stature. To attain accurate diagnosis, genetic testing should be recommended for children with a stature of less than -3s and facial dysmorphism. The long-term efficacy of growth hormone therapy for patients with 3M syndrome remains to be observed.

    3M综合征矮身材基因检测生长激素

      原文链接:
    • 万方数据

    B3GALNT2基因变异所致α-抗肌萎缩相关糖蛋白病一个家系的遗传学分析

    曾丽娜林荔张艳林堃...
    802-806页
    查看更多>>摘要：目的 探讨1个2次妊娠均出现胎儿脑积水的家系的遗传学病因。 方法 收集2021年3月8日就诊于莆田学院附属医院1名孕妇的流产胎儿组织及其孕妇夫妇的外周血样，对其进行家系全外显子组测序(WES)，对候选变异进行Sanger测序验证。 结果 胎儿携带B3GALNT2基因c.261-2A>G和c.536T>C(p.Leu179Pro)复合杂合变异，分别遗传自父母，经检索相关数据库国内既往未见报道，该变异可导致α-抗肌萎缩相关糖蛋白病引起胎儿脑积水。根据美国医学遗传学与基因组学学会变异相关指南，c.261-2A>G与c.536T>C均评级为可能致病性变异(PVS1+PM2_Supporting；PM3+PM2_Supporting+PP3+PP4)。 结论 B3GALNT2基因存在c.261-2A>G和c.536T>C(p.Leu179Pro)复合杂合变异为该家系胎儿出现α-抗肌萎缩相关糖蛋白病的致病原因，为家系的遗传咨询和再生育指导提供依据。 Objective To explore the genetic basis for a Chinese pedigree affected with recurrent fetal hydrocephalus. Methods A couple who had presented at the Affiliated Hospital of Putian College on March 3, 2021 was selected as the study subject. Following elective abortion, fetal tissue and peripheral blood samples were respectively obtained from the abortus and the couple, and were subjected to whole exome sequencing. Candidate variants were verified by Sanger sequencing. Results The fetus was found to harbor compound heterozygous variants of the B3GALNT2 gene, namely c. 261-2A>G and c. 536T>C, which were inherited from its father and mother, respectively. According to the guidelines of American College of Medical Genetics and Genomics, both variants were classified as pathogenic (PVS1+ PM2_Supporting PM3+ PM2_Supporting+ PP3+ PP4). Conclusion The compound heterozygous variants of the B3GALNT2 gene probably underlay the α-dystroglycanopathy in this fetus. Above results have provided a basis for genetic counseling of this pedigree.

    α-抗肌萎缩相关糖蛋白病B3GALNT2基因脑积水全外显子组测序

      原文链接:
    • 万方数据

    线粒体tRNA变异与一个冠心病家系的相关性研究

    丁禹俞金芳高贝贝黄进宇...
    807-814页
    查看更多>>摘要：目的 探讨线粒体DNA变异和冠心病的相关性，研究1个母系遗传冠状动脉粥样硬化性心脏病(CHD)的可能机制。 方法 选取2022年5月10日在杭州市第一人民医院就诊的1例女性CHD先证者及其母系遗传CHD家系成员作为研究对象，收集该家系的先证者和母系CHD成员的临床资料。通过对先证者及家系成员进行线粒体DNA测序，对照正常线粒体基因，经过数据比对筛选变异位点。针对变异位点，进行物种间的保守性分析并使用生物信息学软件预测变异位点对tRNA二级结构的影响。Real-time PCR检测线粒体拷贝数，并建立转线粒体细胞系进行线粒体功能分析，包括膜电位和ATP水平测定。 结果 该家系共4代32人，母系成员10人，患CHD有4人，外显率为40%。测序结果发现先证者和母系成员携带m.4420A>T及m.10463T>C变异，2个变异位点在物种间均具有高度保守性。m.4420A>T位于tRNAMet D环第22位碱基上，m.4420A>T变异破坏了原有13T-22A碱基配对，可能会引起tRNA代谢障碍。m.10463T>C位于tRNAArg接收臂的第67位碱基，该位点碱基与tRNA结构稳定性相关。实验发现携带m.4420A>T和m.10463T>C变异的家系成员的线粒体拷贝数、膜电位和ATP水平均低于正常对照(P<0.05)，分别平均下降约50.47%、39.6%及47.4%。 结论 线粒体tRNAMet 4420A>T和tRNAArg 10463T>C变异可能是这个母系CHD家系的重要分子基础。该家系表现出mtDNA同质性变异、发病年龄以及临床表型等差异，提示核基因、环境因素和线粒体遗传背景对家系成员的冠心病发病进程有一定的影响。 Objective To explore the correlation of mitochondrial DNA (mtDNA) variants and coronary heart disease (CHD) in a Chinese pedigree and the possible molecular mechanisms. Methods A Chinese pedigree featuring matrilineal inheritance of CHD who visited Hangzhou First People′s Hospital in May 2022 was selected as the study subject. Clinical data of the proband and her affected relatives was collected. By sequencing the mtDNA of the proband and her pedigree members, candidate variants were identified through comparison with wild type mitochondrial genes. Conservative analysis among various species was conducted, and bioinformatics software was used to predict the impact of variants on the secondary structure of tRNA. Real-time PCR was carried out to determine the copy number of mtDNA, and a transmitochondrial cell line was established for analyzing the mitochondrial functions, including membrane potential and ATP level. Results This pedigree had contained thirty-two members from four generations. Among ten maternal members, four had CHD, which yielded a penetrance rate of 40%. Sequence analysis of proband and her matrilineal relatives revealed the presence of a novel m. 4420A>T variant and a m. 10463T>C variant, both of which were highly conserved among various species. Structurally, the m. 4420A>T variant had occurred at position 22 in the D-arm of tRNAMet, which disrupted the 13T-22A base-pairing, while the m. 10463T>C variant was located at position 67 in the acceptor arm of tRNAArg, a position critical for steady-state level of the tRNA. Functional analysis revealed that patients with the m. 4420A>T and m. 10463T>C variants exhibited much fewer copy number of mtDNA and lower mitochondrial membrane potential (MMP) and ATP contents (P< 0.05), which were decreased by approximately 50.47%, 39.6% and 47.4%, respectively. Conclusion Mitochondrial tRNAMet 4420A>T and tRNAArg 10463T>C variants may underlay the maternally transmitted CHD in this pedigree, which had shown variation in mtDNA homogeneity, age of onset, clinical phenotype and other differences, suggesting that nuclear genes, environmental factors and mitochondrial genetic background have certain influence on the pathogenesis of CHD.

    冠心病母系遗传线粒体tRNA基因变异家系

      原文链接:
    • 万方数据

    山西运城地区新生儿听力与耳聋基因联合筛查结果分析

    何红琴苏力徐佳王一雯...
    815-820页
    查看更多>>摘要：目的 分析山西运城地区6 723例新生儿听力及耳聋基因筛查结果，了解该地区耳聋基因常见的变异类型。 方法 回顾性分析2021年1月1日至2021年12月31日在运城地区出生的6 723例新生儿进行听力学检查结果，包括瞬态诱发耳声发射和自动判别听性脑干诱发电位，凡其中一项筛查未通过者，均视为复查未通过。采用遗传性耳聋相关基因检测试剂盒对GJB2、SLC26A4、GJB3和mtDNA12S rRNA等我国常见耳聋变异基因的15个热点变异位点进行检测。听力学复查检查通过组与未通过组组间比较采用χ2检验。 结果 6 723例新生儿中，听力初筛通过6 456例(96.03%)，267例初筛未通过新生儿中有244例接受听力复查(91.38%)，14例未通过听力复查，听力复查未通过率5.73%(14/244)，听力障碍患者的大概比例为0.21%(14/6 723)。67 23例新生儿中有363例检出耳聋基因变异，检出率为5.40%(363/6 723)。GJB2基因变异166例，检出率为2.47%(166/6 723)；SLC26A4基因变异136例，检出率为2.02%(136/6 723)；线粒体12S rRNA基因变异26例，检出率为0.39%(26/6 723)；GJB3基因变异33例，检出率为0.49%(33/6 723)。230例复查通过组有10例携带耳聋基因变异，检出率为4.34%(10/230)，14例未通过组有4例携带耳聋基因变异，检出率为28.57%，二组间存在差异(P<0.05)。 结论 新生儿耳聋基因筛查是听力筛查的有效补充，联合筛查是目前防聋筛查的最佳模式。新生儿行听力及耳聋基因联合筛查，可及早发现潜在致聋风险，针对性采取防聋措施、开展遗传咨询，为新生儿提供准确的预后信息。 Objective To analyze the clinical significance of combined newborn hearing and deafness gene screening in Yuncheng area of Shanxi Province. Methods Results of audiological examinations, including transient evoked otoacoustic emission and automatic discriminative auditory brainstem evoked potentials, for 6 723 newborns born in Yuncheng area from January 1, 2021 to December 31, 2021, were retrospectively analyzed. Those who failed one of the tests were considered to have failed the examination. A deafness-related gene testing kit was used to detect 15 hot spot variants of common deafness-associated genes in China including GJB2, SLC26A4, GJB3, and mtDNA 12S rRNA. Neonates who had passed the audiological examinations and those who had not were compared using a chi-square test. Results Among the 6 723 neonates, 363 (5.40%) were found to carry variants. These have included 166 cases (2.47%) with GJB2 gene variants, 136 cases (2.03%) with SLC26A4 gene variants, 26 cases (0.39%) with mitochondrial 12S rRNA gene variants, and 33 cases (0.49%) with GJB3 gene variants. Among the 6 723 neonates, 267 had failed initial hearing screening, among which 244 had accepted a re-examination, for which 14 cases (5.73%) had failed again. This has yielded an approximate prevalence of hearing disorder of 0.21% (14/6 723). Among 230 newborns who had passed the re-examination, 10 (4.34%) were found to have carried a variant. By contrast, 4 out of the 14 neonates (28.57%) who had failed the re-examination had carried a variant, and there was a significant difference between the two groups (P< 0.05). Conclusion Genetic screening can provide an effective supplement to newborn hearing screening, and the combined screening can provide a best model for the prevention of hearing loss, which can enable early detection of deafness risks, targeted prevention measures, and genetic counseling to provide accurate prognosis for the newborns.

    新生儿筛查GJB2基因GJB3基因SLC26A4基因12SrRNA耳聋基因变异听力诊断

      原文链接:
    • 万方数据

    成骨不全胎儿2例的 COL1A1与 COL1A2基因变异分析

    张亚宁吴昕悦刘巧云闫晓娜...
    821-827页
    查看更多>>摘要：目的 探讨2例成骨不全症(OI)胎儿的临床表型及遗传学特征，明确致病原因。 方法 收集分别在2021年6月11日和2021年10月16日就诊于潍坊医学院附属医院的2例中孕期超声诊断疑似OI胎儿的临床资料信息。采集孕妇羊水及胎儿父母、亲属外周血样品提取基因组DNA，对2例胎儿进行全外显子组测序(WES)，对候选变异进行Sanger家系验证。针对可能影响pre-mRNA剪接的变异，利用minigene体外分析变异位点附近外显子的剪接方式，对变异的致病性进行判定。 结果 胎儿1在胎龄17+6周超声显示双侧肱骨和股骨发育落后2周余，四肢长骨多发骨折、成角畸形。胎儿2在胎龄23周超声显示双侧肱骨和股骨发育分别落后1+周和4周，双侧股骨和胫腓骨弯曲。WES结果显示胎儿1的COL1A1基因第49外显子存在c.3949_3950insGGCATGT(p.N1317Rfs*114)杂合变异，该变异导致翻译提前终止，胎儿父母外周血中未检出该变异。根据美国医学遗传学与基因组学学会(ACMG)变异评级指南，c.3949_3950insGGCATGT变异评级为致病性变异(PVS1+PS2+PM2_Supporting)。胎儿2的COL1A2基因第26内含子中存在父源的c.1557+3A>G杂合变异，剪接报告基因分析提示该变异使COL1A2基因pre-mRNA第26外显子发生跳跃，导致mRNA转录本第1 504~1 557位编码序列整码缺失及其编码蛋白第502~519位氨基酸缺失，根据ACMG变异评级指南，c.1557+3A>G杂合变异评级为致病性变异(PS3+PM1+PM2_Supporting+PP3+PP5)。 结论 COL1A1基因c.3949_3950insGGCATGT变异、COL1A2基因c.1557+3A>G变异分别可能为2例OI胎儿的遗传学原因。COL1A1基因c.3949_3950insGGCATGT的发现丰富了成骨不全致病基因变异谱。 Objective To explore the genetic basis of two fetuses with an osteogenesis imperfecta (OI) phenotype. Methods Two fetuses diagnosed at the Affiliated Hospital of Weifang Medical College respectively on June 11, 2021 and October 16, 2021 were selected as the study subjects. Clinical data of the fetuses were collected. Amniotic fluid samples of the fetuses and peripheral blood samples of their pedigree members were collected for the extraction of genomic DNA. Whole exome sequencing (WES) and Sanger sequencing were carried out to identify the candidate variants. Minigene splicing reporter analysis was used to validate the variant which may affect the pre-mRNA splicing. Results For fetus 1, ultrasonography at 17+ 6 weeks of gestation had revealed shortening of bilateral humerus and femurs by more than two weeks, in addition with multiple fractures and angular deformities of long bones. WES revealed that fetus 1 had harbored a heterozygous c. 3949_3950insGGCATGT (p.N1317Rfs*114) variant in exon 49 of the COL1A1 gene (NM_000088.4). Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), it was classified as a pathogenic variant (PVS1+ PS2+ PM2_Supporting) for disrupting the downstream open reading frame resulting in premature translational termination, being de novo in origin, and lacking records in the population and disease databases. For fetus 2, ultrasonography at 23 weeks of gestation also revealed shortening of bilateral humerus and femurs by one and four weeks, respectively, in addition with bending of bilateral femurs, tibias and fibulas. Fetus 2 had harbored a heterozygous c. 1557+ 3A>G variant in intron 26 of theCOL1A2 gene (NM_000089.4). Minigene experiment showed that it has induced skipping of exon 26 from the COL1A2 mRNA transcript, resulting in an in-frame deletion (c.1504_1557del) of the COL1A2 mRNA transcript. The variant was inherited from its father and had been previously reported in a family with OI type 4. It was therefore classified as a pathogenic variant (PS3+ PM1+ PM2_Supporting + PP3+ PP5). Conclusion The c. 3949_3950insGGCATGT (p.N1317Rfs*114) variant in the COL1A1 gene and c. 1557+ 3A>G variant in theCOL1A2 gene probably underlay the disease in the two fetuses. Above findings not only have enriched the mutational spectrum of OI, but also shed light on the correlation between its genotype and phenotype and provided a basis for genetic counseling and prenatal diagnosis for the affected pedigrees.

    成骨不全COL1A1基因COL1A2基因全外显子组测序mRNA剪接异常胎儿

      原文链接:
    • 万方数据

    Williams-Beuren综合征患儿2例的临床特征及遗传学分析

    黄明珠徐玲玲陈晓媛董玲花...
    828-832页
    查看更多>>摘要：目的 探讨2例Williams-Beuren综合征(WBS)患儿的临床及遗传学特征。 方法 将2例分别于2021年1月26日与2021年3月18日就诊于宁夏医科大学总医院儿科的患儿作为研究对象。分析患儿的临床资料，并对其进行基因检测。 结果 2例患儿均表现为生长发育迟缓、特殊面容及心血管异常。患儿1合并有亚临床甲减，患儿2合并有癫痫发作。基因检测发现患儿1染色体7q11.23区存在1.54 Mb缺失，患儿2染色体7q11.23区存在1.53 Mb缺失，同时存在ATP1A1基因的c.158G>A变异和KMT2C基因的c.12181A>G变异。根据美国医学遗传学与基因组学学会相关指南，c.158G>A与c.12181A>G变异评级为意义未明变异(PM1+PM2_Supporting+PP2+PP3；PM2_Supporting)。 结论 2例患儿具有WBS综合征的典型表现，染色体7q11.23区微缺失是其主要的病因。对存在生长发育迟滞、特殊面容以及心血管畸形的患儿，需考虑WBS，并通过基因检测明确诊断。 Objective To explore the clinical and genetic characteristics of two children with Williams-Beuren syndrome(WBS). Methods Two children who had presented at the Department of Pediatrics, General Hospital of Ningxia Medical University respectively on January 26 and March 18, 2021 were selected as the study subjects. Clinical data and results of genetic testing of the two patients were analyzed. Results Both children had featured developmental delay, characteristic facies and cardiovascular malformation. Child 1 also had subclinical hypothyroidism, whilst child 2 had occurrence of epilepsy. Genetic testing revealed that child 1 has harbored a 1.54 Mb deletion in the 7q11.23 region, whilst child 2 has a 1.53 Mb deletion in the same region, in addition with a c. 158G>A variant of theATP1A1 gene and a c. 12181A>G variant of theKMT2C gene. Based on the guidelines from the American College of Medical Genetics and Genomics, the c. 158G>A and c. 12181A>G variants were rated as unknown significance variants (PM1+ PM2_Supporting+ PP2+ PP3 PM2_Supporting). Conclusion Both children had characteristic features of WBS, for which deletions of the 7q11.23 region may be accountable. For children manifesting developmental delay, facial dysmorphism and cardiovascular malformations, the diagnosis of WBS should be suspected, and genetic testing should be recommended to confirm the diagnosis.

    Williams-Beuren综合征染色体微缺失临床表型癫痫基因

      原文链接:
    • 万方数据

    Kabuki综合征患儿2例的基因变异及临床表型分析

    沈裕孙淑妮解敏李海波...
    833-837页
    查看更多>>摘要：目的 探讨2例KMT2D基因变异所致Kabuki综合征(KS)的患儿，并总结其临床特征与基因变异的特点。 方法 以分别于2021年8月19日和11月10日就诊于宁波市妇女儿童医院的2例KS患儿作为研究对象，收集其临床资料，对其进行全外显子组测序(WES)，并对候选变异进行Sanger测序家系验证。 结果 2例患儿均表现为运动、语言发育迟缓、特殊面容、智力障碍等。WES检测发现其分别携带KMT2D基因的c.10205del(p.Leu3402Argfs*3)及c.5104C>T(p.Arg1702*)杂合变异，根据美国医学遗传学和基因组学学会相关指南均评估为致病性变异(PVS1+PM6+PM2_Supporting+PP4)。 结论 KMT2D基因的c.10205del(p.Leu3402Argfs*3)和c.5104C>T(p.Arg1702*)新发变异可能是2例KS患儿的遗传学病因。上述发现不仅为临床确诊和遗传咨询提供了依据，并且丰富了KMT2D基因的变异谱。 Objective To report on two children with Kabuki syndrome due to variants of the KMT2D gene and summarize their clinical and genetic characteristics. Methods Two children who had presented at the Ningbo Women and Children′s Hospital respectively on August 19 and November 10, 2021 were selected as the study subjects. Clinical data were collected. Both children were subjected to whole exome sequencing (WES), and candidate variants were validated by Sanger sequencing. Results Both children had featured motor and language developmental delay, facial dysmorphism and mental retardation. Genetic testing revealed that both had harbored de novo heterozygous variants of the KMT2D gene, namely c. 10205del (p.Leu3402Argfs*3) and c. 5104C>T (p.Arg1702*), both of which were rated as pathogenic variants(PVS1+ PM6+ PM2_Supporting+ PP4) based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). Conclusion The c. 10205del (p.Leu3402Argfs*3) and c. 5104C>T (p.Arg1702*) variants of theKMT2D gene probably underlay the pathogenesis in these two children. Above finding has not only provided a basis for their diagnosis and genetic counseling, but also enriched the spectrum of KMT2D gene variants.

    Kabuki综合征生长发育迟缓KMT2D基因新发变异

      原文链接:
    • 万方数据