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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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    极长链酰基辅酶A脱氢酶缺乏症1个家系的报道并文献复习

    蔡世岩杨俊逸王诗宇陈红...
    59-66页
    查看更多>>摘要：目的 探讨中国籍极长链酰基辅酶A脱氢酶缺乏症(VLCADD)患儿的临床分型与基因型和预后之间的相关性。 方法 对本院2019年2月接诊的1个VLCADD家系进行回顾性总结，分析其发病特点、诊治过程及预后，并对相关文献进行回顾。 结果 患儿，男，1岁，主要表现为频繁发作的呕吐、低血糖、肝功能及心肌酶异常。足跟血串联质谱筛查显示C14、C14：1、C16：1、C16：2、C18和C14/C8明显升高，基因检测发现患儿ACADVL基因存在c.664G>A(p.G222R)和c.1345G>A(p.E449K)复合杂合变异，分别来源于父亲和母亲，患儿被确诊为VLCADD，临床分型为心肌病型。患儿于入院2周后死亡。结合文献报道，共收集60例中国籍VLCADD患儿的资料，其临床分型以心肌病型和肝病型为主，占比达73.3%(43/60)；基因变异组合类型与临床分型有一定的相关性，心肌病型患儿多携带2个功能丧失突变(LOF)；心肌病型预后最差，死亡率高达76.9%(20/26)。C14：1作为诊断VLCADD的敏感指标，无法用于临床分型和预后评估。c.1349G>A(p.R450H)变异频次最高，占10.8%(13/120)。 结论 VLCADD的临床分型与预后高度相关。LOF变异在临床表现严重的患儿中更为常见。c.1349G>A(p.R450H)变异可能是中国人群中最常见的变异，早期筛查和诊断可以极大改善患儿的预后。 Objective To explore the correlation between clinical classification and genotype and prognosis among Chinese children with Very-long chain acyl-CoA dehydrogenase deficiency (VLCADD). Methods A Chinese pedigree affected with VLCADD admitted at the First People′s Hospital of Yunnan Province in February 2019 was selected as the study subject. The characteristics of disease onset, diagnosis and treatment and prognosis were retrospectively analyzed. Relevant literature was also systematically searched and reviewed. Results The proband, a 1-year-old boy, had the clinical manifestations of frequently vomiting, hypoglycemia, abnormal liver function and myocardial enzymes. Tandem mass spectrometry screening showed significantly elevated C14, C14: 1, C16: 1, C16: 2, C18 and C14/C8. Genetic testing revealed that he has harbored compound heterozygous variants of the ACADVL gene, namely c. 664G>A (p.G222R) and c. 1345G>A (p.E449K), which were respectively derived from his father and mother. The child was diagnosed with VLCADD cardiomyopathy type and deceased 2 weeks later. Literature review has identified 60 Chinese children with VLCADD. The clinical classifications were mainly cardiomyopathy type and liver disease type, which accounted for 73.3% (43/60). The combination ofACADVL gene variants were correlated with the clinical classifications of VLCAD. Children with one or two loss-of-function (LOF) mutations showed more severe clinical manifestation and a higher mortality. Cardiomyopathy type had the poorest prognosis, with a mortality rate of 76.9% (20/26). C14: 1 may be used as an indicator for the diagnosis of VLCADD, but cannot be used for clinical subtyping and prognosis evaluation. The c. 1349G>A (p.R450H) variant had the highest frequency among the Chinese patients, accounting for 10.8% (13/120). Conclusion The clinical classifications of VLCADD are strongly correlated with the prognosis, and LOF mutations are more common in those with severe clinical manifestations. c. 1349G>A (p.R450H) may be the most common variant among the Chinese patients, and early screening and diagnosis can greatly improve the prognosis of patients.

    极长链酰基辅酶A脱氢酶ACADVL基因极长链脂肪酸线粒体脂肪酸β氧化

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    ARID1B基因变异致Coffin-Siris综合征2例患儿的遗传学分析

    李治刘芳万瑞华吴园园...
    67-74页
    查看更多>>摘要：目的 分析2例无明显原因精神运动发育迟缓、面容异常的患儿的基因特征，加强对Coffin-Siris综合征(CSS)的认识与了解。 方法 选取2019年7月至2021年1月因"发育迟缓"就诊于中国人民解放军联勤保障部队第九八〇医院新生儿科的2例CSS患儿，其中男性1例，女性1例，及其家系成员2代，共计7人作为研究对象。收集患儿及家庭成员的临床资料和家族史，对患儿进行详细的体格检查，完善实验室及相关辅助检查。对患儿及其父母进行全外显子组测序(WES)和基因组拷贝数变异测序(CNV-seq)，确认变异基因位点及拷贝数变异(CNV)。 结果 患儿1为8月龄女性，存在小头畸形、房间隔缺损、第五指/趾侧弯、四肢肌张力低下。患儿2为2岁6个月男性，存在语言迟缓、社交障碍、毛发浓密，第五指无弯曲。基因检测发现患儿1在ARID1B基因存在第8～21外显子杂合缺失，家系验证显示其父母均为野生型，考虑为新发变异。根据美国医学遗传学与基因组学学会(ACMG)和美国分子病理学会发布的序列变异解读标准和指南，该变异评级为致病性变异(PVS1＋PS2＋PM2_Supporting)。患儿2的ARID1B基因存在1个杂合变异c.4263-6(IVS17)T>G，转录组测序结果显示该变异会影响正常剪接，致第17内含子中5 bp序列滞留，家系验证显示其父母均为野生型，考虑为新发变异。根据ACMG变异标准与指南，c.4263-6(IVS17)T>G评级为致病性变异(PS2＋PM2_Supporting＋PP3＋PS3)。 结论 利用WES和CNV-seq技术确诊了2例CSS患儿，发现的变异拓展了CSS新的致病基因变异谱，为家庭遗传咨询提供了可靠的依据。 Objective To explore the genetic basis of two children with unexplained psychomotor developmental delay and facial dysmorphisms suggestive of Coffin-Siris syndrome (CSS). Methods A boy and a girl suspected for CSS at the 980th Hospital of the People′s Liberation Army Joint Service Support Force respectively in July 2019 and January 2021, and seven members from their families, were selected as the study subjects. Clinical data and family history of the children were collected, and detailed physical examination was carried out, in addition with laboratory and related auxiliary examinations. Potential variants and copy number variations (CNVs) were detected by whole exome sequencing (WES) and copy number variation sequencing (CNV-seq). Results Child 1, an 8-month-old female, had featured microcephaly, atrial septal defect, curving of fifth finger/toe, and low limb muscle tone. Child 2 was a 2.5-year-old male with language delay, social impairment, dense hair but no curving of the fifth fingers. Genetic testing revealed that child 1 had loss of heterozygosity for exons 8 to 21 of the ARID1B gene, which was unreported previously. Family verification showed that both of her parents were of the wild type. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG) and American Society of Molecular Pathology (AMP), the variant was rated as pathogenic (PVS1+ PS2+ PM2-supporting). Child 2 was found to harbor a heterozygous c. 4263-6 (IVS17) T>G variant of the ARID1B gene. Transcriptome sequencing confirmed that the variant can affect the normal splicing, resulting in retention of a 5 bp sequence in intron 17. Family verification showed that both of his parents were of the wild type. Based on the guidelines from the ACMG, the variant was rated as pathogenic (PS2+ PM2-supporting+ PP3+ PS3). Conclusion WES and RNA-seq have confirmed the diagnosis of CSS in both children. Discovery of the novel variants has expanded the spectrum of pathogenic mutations underlying CSS, and provided a basis for the genetic counseling.

    ARID1B基因Coffin-Siris综合征随访研究儿童

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    CLN1型神经元蜡样脂褐质沉积症伴遗传性高铁蛋白血症-白内障综合征1例患儿的分析

    周凡王建东王瑶李海英...
    75-80页
    查看更多>>摘要：目的 分析1例神经元蜡样脂褐质沉积症1型(CLN1)合并遗传性高铁蛋白血症-白内障综合征(HHCS)患儿的临床及遗传学特征。 方法 以2020年11月郑州大学第一附属医院收治的1例患儿作为研究对象。收集患儿的临床资料，对其进行基因检测，并结合文献回顾分析其临床和遗传变异的特点，为早期识别提供思路。 结果 患儿　男，3岁，以视力损害、进行性认知和运动功能倒退、癫痫发作为主要表现。磁共振成像提示双侧大脑半球脑沟加深、髓鞘发育明显落后。棕榈酰蛋白硫酯酶活力偏低(8.4 nmol/g/min，正常参考值：132.2 ～ 301.4 nmol/g/min)，血清铁蛋白升高(2 417.70 ng/mL，正常参考值：30 ～ 400 ng/mL)。眼底成像示视网膜色素变性。全外显子测序发现患儿PPT1基因存在c.280A>C及c.124-124＋3delG复杂杂合突变，分别遗传自父亲和母亲，二者既往均未见报道。此外，其FTL基因存在c.-160A>G杂合变异，遗传自父亲。结合患儿的临床表型和遗传变异，诊断其为CLN1和HHCS。 结论 PPT1基因的c.280A>C和c.124-124＋3delG复合杂合变异及FTL基因的c.-160A>C变异可能是患儿的遗传学病因。临床对于视力损害进展较快的CLN1患儿，应进一步完善眼科检查并详细询问家族史，对高度怀疑合并HHCS的患儿应尽早通过基因检测确诊。 Objective To analyze the clinical data and genetic characteristics of a child with CLN1 neuronal ceroid lipofuscinosis in conjunct with hereditary hyperferritinemia cataract syndrome (HHCS). Methods A child who was admitted to the PICU of the First Affiliated Hospital of Zhengzhou University in November 2020 was selected as the study subject. Clinical data of the child was collected. Genetic testing was carried out for the child, and the result was analyzed in the light of literature review to explore the clinical and genetic characteristics to facilitate early identification. Results The patient, a 3-year-old male, had mainly presented with visual impairment, progressive cognitive and motor regression, and epilepsy. Cranial magnetic resonance imaging revealed deepened sulci in bilateral cerebral hemispheres, and delayed myelination. The activity of palmitoyl protein thioesterase was low (8.4 nmol/g/min, reference range: 132.2 ~ 301.4 nmol/g/min), whilst serum ferritin was increased (2 417.70 ng/mL, reference range: 30 ~ 400 ng/mL). Fundoscopy has revealed retinal pigment degeneration. Whole exome sequencing revealed that he has harbored c. 280A>C and c. 124-124+ 3delG compound heterozygous variants of thePPT1 gene, which were respectively inherited from his father and mother. Neither variant has been reported previously. The child has also harbored a heterozygous c. -160A>G variant of theFTL gene, which was inherited from his father. Based on the clinical phenotype and results of genetic testing, the child was diagnosed as CLN1 and HHCS. Conclusion The compound heterozygous variants of the PPT1 gene probably underlay the disorders in this child. For children with CLN1 and rapidly progressing visual impairment, ophthalmological examination should be recommended, and detailed family history should be taken For those suspected for HHCS, genetic testing should be performed to confirm the diagnosis.

    神经元蜡样脂褐质沉积症PPT1基因高铁蛋白血症白内障综合征FTL基因

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    KDM6A基因突变致歌舞伎综合征胎儿的1个三代家系的临床特征及遗传咨询

    梁业琼安宇李岭
    81-85页
    查看更多>>摘要：目的 探讨1例具有不良孕产史的女性的遗传学病因。 方法 以1例曾有1次胎停和2次横膈疝伴心脏复杂畸形胎儿引产史的女性作为研究对象，采集其第2次引产儿的组织，提取基因组DNA进行全外显子组测序，对候选变异进行Sanger测序家系验证。 结果 测序发现胎儿的KDM6A基因存在c.1228_1229del(p.Gln410GlufsTer2)半合子移码终止变异，既往未见报道。根据美国医学遗传学与基因组学学会相关指南判断为可能致病(PVS1＋PM2_Supporting)。该变异可导致歌舞伎综合征2型。孕妇及其母亲均携带相同的变异。孕妇身材矮小、眉毛外1/3稀疏，智力正常，存在女性生殖器官先天性发育异常(阴道不完全纵膈、双宫颈、双子宫和单侧卵巢缺失)，其外祖母表型大部分相似。对胎儿的产前影像学表型进行描述，对孕妇持续随访，探讨其在社区随访实践中的疾病管理策略。 结论 KDM6A基因的c.1228_1229del(p.Gln410GlufsTer2)变异可能是导致胎儿膈疝伴心脏结构畸形的遗传学病因。歌舞伎综合征2型胎儿的超声表型以及携带者双子宫畸形既往报道很少。本研究丰富了上述表型谱，为临床诊断和遗传咨询提供了依据。 Objective To explore the genetic basis for a pregnant woman with a history of adverse pregnancy outcomes. Methods A woman with an adverse history of pregnancies including one fetal demise and two induced abortions due to fetal diaphragmatic hernia and complex cardiac anomalies was selected as the study subject. Muscle tissue from the induced abortus was subjected to whole exome sequencing, and candidate variant was verified by Sanger sequencing of the couple and other family members. Results Genetic sequencing revealed that the fetus has harbored a frameshift variant of the KDM6A gene (NM_001291415.2), namely c. 1228_1229del (p.Gln410GlufsTer2), which was inherited from the woman and her mother. The variant was unreported previously, and the woman was found to have short stature, sparse eyebrows in the outer third, peculiar facial features, but normal intelligence in addition with female congenital genital malformation, like incomplete vaginal septum, double cervix, double uterus, and unilateral ovary absence. mostly similar phenotypes observed in her mother. Conclusion The hemizygous c. 1228_1229del variant of the KDM6A gene probably underlay the abnormalities in the fetus. All findings have enabled genetic counseling for this family featuring X-linked inheritance, and the woman had given birth to a healthy girl with appropriate prevention and intervention.

    歌舞伎综合征KDM6A基因变异全外显子组测序双子宫

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    HNRNPU基因变异致神经发育障碍患儿1例并文献回顾

    尹雪周俊易海英杨树杰...
    86-91页
    查看更多>>摘要：目的 探讨1例HNRNPU基因变异导致神经发育障碍(NDDs)患儿的临床表现及基因变异特征，并检索文献进行回顾性分析。 方法 回顾性分析2020年12月至武汉科技大学附属孝感医院就诊的1例因"间断抽搐1年余"NDDs患儿的临床资料，收集患儿及其父母的外周血样，进行全外显子组测序并进行Sanger测序验证。以"HNRNPU基因""癫痫""癫痫性脑病""遗传性癫痫""神经发育障碍""神经发育综合征"与"epilepsy""epileptic encephalopathy""hereditary epilepsy""neurodevelopmental disorders""neurodevelopmental syndrome""HNRNPU""NDDs"为中英文关键词，检索时间设定为1994年1月1日至2022年2月10日，检索中国知网、万方数据库及PubMed数据库中相关文献并作总结复习。 结果 患儿为2岁男性，5月龄起病，临床表型主要为外貌异常、反复癫痫发作、Gesell量表评估各能区发育商偏低。给予患儿丙戊酸钠抗癫痫发作治疗及康复训练，随访半年内无癫痫发作，但智能及运动发育无明显改善。基因检测患儿HNRNPU基因存在c.1720_1722delCTT(p.Lys574del)杂合变异，父母未见该变异。根据美国医学遗传学与基因组学学会变异相关指南，c.1720_1722delCTT评级为可能致病性变异(PS2＋PM2_Supporting＋PM4)。文献检索到13篇文献，HNRNPU基因变异类型有剪接点变异、无义变异、错义变异、框内缺失、基因重复、移码变异、多个外显子缺失。主要临床表现有发育迟缓、癫痫、智力低下、语言发育落后、颅面畸形、精神行为异常等。 结论 HNRNPU：c.1720_1722delCTT考虑为该NDDs患儿的致病原因。基因检测有助于儿童NDDs的诊断，变异发现丰富了HNRNPU基因变异致神经发育障碍基因变异谱。 Objective To explore the clinical characteristics and genetic variant in a child with neurodevelopmental disorders (NDDs). Methods Clinical data of a child who had presented at Xiaogan Hospital Affiliated to Wuhan University of Science and Technology in December 2020 due to intermittent convulsions for over a year were retrospectively analyzed. Peripheral blood samples of the child and his parents were collected and subjected to whole exome sequencing. Candidate variants were verified by Sanger sequencing and bioinformatic analysis. " HNRNPU gene", "epilepsy", "epileptic encephalopathy", "hereditary epilepsy", "neurodevelopmental disorder", "neurodevelopmental syndrome", "HNRNPU", and "NDDs" were used as the key words to search the CNKI, Wanfang and PubMed databases dated from January 1, 1994 to February 10, 2022. Results The patient was a 2-year-old boy who had developed seizure at the age of 5 months. His clinical features had included abnormal appearance, recurrent seizures, and low developmental quotients of each functional area as evaluated by the Gesell scale. The child was given sodium valproate for the antiepileptic treatment and rehabilitation training. He had become seizure-free within half a year of follow-up, but his intelligence and motor development did not improve significantly. Genetic testing revealed that he has harbored a heterozygous c. 1720_1722delCTT (p.Lys574del) variant of the HNRNPU gene, which was not found in either of his parents. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was rated as likely pathogenic (PS2+ PM2_Supporting+ PM4). A total of 13 articles were retrieved, and the types of HNRNPU gene mutations have included splice site mutation, nonsense mutation, missense mutation, in-frame deletion, gene duplication, frameshifting mutation, and multiple exon deletion. The main clinical manifestations have included mental retardation, language delay, global developmental delay, epilepsy, craniofacial deformity, mental and behavioral abnormalities. Conclusion The c. 1720_1722delCTT variant of the HNRNPU gene probably underlay the NDDs in this child. Above finding has enriched the mutational spectrum of the HNRNPU gene.

    神经发育障碍HNRNPU基因儿童

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    心脏瓣膜发育不全1型胎儿1例的临床表型及遗传学分析

    闫露露曹娟张玉鑫李冬梅...
    92-95页
    查看更多>>摘要：目的 分析1例心脏瓣膜发育不全1型(CVDP1)引产胎儿的遗传学病因。 方法 选取2022年7月7日在宁波市妇女儿童医院就诊的1例CVDP1胎儿为研究对象。收集胎儿的临床资料。应用家系全外显子组测序(trio-WES)技术对胎儿及父母进行致病基因检测，针对可疑致病变异，进行Sanger测序家系验证。 结果 胎儿表现为全身水肿、心脏复杂畸形、腹腔积液、肠管回声增强及双肾实质回声增强。WES结果显示胎儿携带PLD1基因c.2977C>T(p.R993*)和c.1460G>A(p.W487*)复合杂合变异，分别遗传自其父母。2个变异既往均未见报道。根据美国医学遗传学与基因组学学会遗传变异标准和指南，c.2977C>T(p.R993*)变异评估为可能致病性(PVS1_Moderate＋PM2_Supporting＋PM3＋PP4)，c.1460G>A(p.W487*)变异评估为致病性(PVS1＋PM2_Supporting＋PP4)。 结论 PLD1基因c.2977C>T(p.R993*)和c.1460G>A(p.W487*)复合杂合变异可能为本研究胎儿的遗传学病因。新变异位点的发现丰富了PLD1基因变异谱，并为该家系的遗传咨询和产前诊断提供了指导。 Objective To explore the genetic basis for a fetus with Cardiac valvular dysplasia type 1 (CVDP1). Methods A CVDP1 fetus identified at the Ningbo Women and Children′s Hospital on July 7, 2022 was selected as the study subject. Clinical data of the fetus was collected. The fetus and its parents were subjected to trio-whole exome sequencing (trio-WES), and candidate variants were verified by Sanger sequencing. Results The fetus had exhibited generalized edema, complex cardiac malformation, abdominal effusion, and enhanced intestinal and renal parenchymal echoes. Trio-WES revealed that it has harbored compound heterozygous variants of the PLD1 gene, namely c. 2977C>T (p.R993*) and c. 1460G>A (p.W487*), which were respectively inherited from its father and mother. Neither variant was reported previously. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c. 2977C>T (p.R993*) variant was evaluated to be likely pathogenic (PVS1_Moderate+ PM2_Supporting+ PM3+ PP4), whilst the c. 1460G>A (p.W487*) variant was evaluated to be pathogenic (PVS1+ PM2_Supporting+ PP4). Conclusion The c. 2977C>T (p.R993*) and c. 1460G>A (p.W487*) compound heterozygous variants of thePLD1 gene probably underlay the CVDP1 in the fetus. Above discovery has enriched the mutational spectrum of the PLD1 gene and provided a guidance for genetic counseling and prenatal diagnosis in this family.

    心脏瓣膜发育不全1型全外显子组测序PLD1基因复合杂合变异

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    以下肢活动后肌痛起病的结蛋白病患者1例的临床及遗传学研究

    吴积宝易继平朱雯华岳冬曰...
    96-100页
    查看更多>>摘要：目的 探讨1例非典型症状起病的结蛋白病患者的临床特点与基因变异情况。 方法 选取2021年2月24日于上海市静安区中心医院神经内科就诊的1例男性结蛋白病患者为研究对象，分析患者的临床资料、实验室检查、肌肉病理、肌肉MRI特点及基因变异情况。 结果 患者以下肢活动后肌痛起病，逐渐出现下肢不对称肌无力、肌肉萎缩，心脏检查提示房室传导阻滞和左室舒张功能减退。肌肉MRI提示除半腱肌、缝匠肌、股薄肌、腓骨肌及腓肠肌受累外，前臂旋后肌早期出现选择性受累。肌肉活检证实为结蛋白阳性肌原纤维病病理改变。基因检测发现DES基因第6外显子存在c.1024A>G错义变异，导致氨基酸p.N342D改变。根据美国医学遗传学与基因组学学会(ACMG)相关指南，该变异评定为可能致病性(PS4_Moderate＋PM2_Supporting＋PP3_Moderate＋PP1)。 结论 结蛋白病有较大临床异质性，下肢运动后肌痛无力是N342D携带者少见的一种临床表型，心脏受累较为隐匿，临床中易被忽视，及时进行肌肉MRI、肌肉活检及基因检测将有助于该病的早期诊断。 Objective To explore the clinical characteristics and genetic variant of a patient with desminopathy manifesting with atypical symptoms. Methods A patient who was admitted to the Department of Neurology of Jing′an District Central Hospital on February 24, 2021 was selected as the study subject. Clinical data, laboratory tests, muscle pathology, muscle magnetic resonance imaging (MRI) and genetic testing of the patient were retrospectively analyzed. Results The patient had developed myalgia after lower limb activity, and gradually developed asymmetrical muscle weakness and atrophy of the lower limbs. Cardiac examination revealed atrioventricular block and decreased left ventricular diastolic function. Muscle MRI showed that semitendinosus, sartorius, gracilis, fibula, gastronemius and supinator muscles were selectively involved at the early stage. Muscle biopsy confirmed pathological changes of desmin positive myofibrils. Genetic testing revealed that the patient has harbored a c. 1024A>G (p.n342d) missense variant in exon 6 of theDES gene. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was rated as likely pathogenic (PS4_moderate+ PM2_supporting+ PP3_moderate+ PP1). Conclusion Desmin disease has a great clinical heterogeneity. Postexercise myalgia of lower limbs is a rare clinical phenotype. For patients harboring the c. 1024A>G (p.n342d) variant of theDES gene, in addition to semitendinosus and fibula, Cardiac involvement is relatively insidious and easy to be ignored in clinic. Timely muscle MRI, muscle biopsy and gene detection will help the early diagnosis of the disease.

    结蛋白病肌原纤维病DES基因远端肌病

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    复杂的嵌合型18号染色体结构异常1例的遗传学分析

    邵敏杰严智强朱小辉闫丽盈...
    101-105页
    查看更多>>摘要：目的 探讨1例嵌合型18号染色体结构异常患者的核型。 方法 选取2019年10月因"结婚4年，未避孕未育2＋年"就诊于北医三院生殖中心的1例不育症男性患者作为研究对象，收集其临床资料。取患者外周血样进行染色体核型分析、拷贝数变异(CNV)分析、荧光原位杂交(FISH)检测，同时取患者的精液样本进行单精子CNV分析。 结果 经检测，确定患者核型为mos 47，XY，del(18)(q21q23)，＋r(18)(q21q23)[84]/46，XY，del(18)(q21q23)[9]/48，XY，del(18)(q21q23)，＋r(18)(q21q23)×2[6]/47，XY，del(18)(q21q23)，＋r(18)(q21q23×2)[1]．ish 47，XY，del(18)(q21q23)，＋r(18)(q21q23)[84]/46，XY，del(18)(q21q23)[9]/48，XY，del(18)(q21q23)，＋r(18)(q21q23)×2[6]/47，XY，del(18)(q21q23)，＋r(18)(q21q23×2)[1]del(18)(q21q23)(D18Z1＋，18p＋，18q＋，WCP18＋)，r(18)(q21q23)(WCP18＋)，r(18)(q21q23×2)(WCP18＋)，CNV分析结果未见异常。单精子测序分析发现18条精子中9条为del(18q)(9/20)，7条为dup(18q)×2(7/20)，2条为dup(18q)×3(2/20)，重复或缺失片段大小均为33 Mb。 结论 该患者携带的18号染色体结构合并数目异常临床比较罕见，尤其是在表型正常的携带者中检测到。通过细胞和分子遗传学的精准诊断，结合单精子拷贝数变异分析，可以进一步评估异常核型对配子生成的影响，从而对生育策略进行精准咨询。 Objective To determine the karyotype of a patient with mosaicism complex structural aberration of chromosome 18. Methods A male patient with a 2-year history of infertility presented at the Center of Reproductive Medicine of the Third Hospital of Peking University in October 2019 was selected as the study subject. Clinical data of the patient was collected. Peripheral blood sample was taken for chromosomal karyotyping, copy number variation (CNV) analysis and fluorescence in situ hybridization (FISH) assay. Semen sample was taken for single sperm CNV analysis. Results The patient was found to have a karyotype of mos 47, XY, del(18)(q21q23), + r(18)(q21q23)[84]/46, XY, del(18)(q21q23)[9]/48, XY, del(18)(q21q23), + r(18)(q21q23)×2[6]/47, XY, del(18)(q21q23), + r(18)(q21q23×2)[1]. ish 47, XY, del(18)(q21q23), + r(18)(q21q23)[84]/46, XY, del(18)(q21q23)[9]/48, XY, del(18)(q21q23), + r(18)(q21q23)×2[6]/47, XY, del(18)(q21q23), + r(18)(q21q23×2)[1]del(18)(q21q23)(D18Z1+, 18p+, 18q+, WCP18+ ), r(18)(q21q23)(WCP18+ ), r(18)(q21q23×2)(WCP18+ ). No pathogenic CNV was identified. Sequencing of 20 single sperms showed that 1 sperm was normal, 1 had yielded no result, 9 had harbored del(18q), 7 had harbored dup(18q)×2, and 2 had harbored dup(18q)×3. The dup/del fragments had both spanned approximately 33 Mb. Conclusion It is rare for carriers of complex structural and numerical abnormalities of chromosome 18 to have a normal phenotype. Based on the accurate cytogenetic and molecular analyses and the single sperm CNV analysis, the influence of the aberrant karyotype on the gametogenesis may be evaluated.

    18号环状染色体18号染色体长臂缺失单精子拷贝数变异分析

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    脊髓性肌萎缩病情监测生物标志物的研究进展

    翦烨敏吴丽文鞠翠钰
    106-112页
    查看更多>>摘要：脊髓性肌萎缩(SMA)是儿童最常见的神经肌肉病，严重影响儿童的生命健康。目前SMA的基因和分子修饰治疗已成为热点，然而SMA患者何时开始治疗、治疗效果以及疾病预后都有许多不确定性，因此迫切需要可靠的生物标志物进行监测和评估。本文将近年来SMA生物标志物研究取得的进展进行综述。 Spinal muscular atrophy (SMA) is the most common neuromuscular disease in children, which seriously affects children′s health. At present, gene and molecular modification therapy for SMA have become hot spots. However, there are many uncertainties about when people with SMA should start treatment, how well the drugs can treat, and the prognosis. Therefore, reliable biomarkers for monitoring and evaluation are urgently needed. This review will summarize the progress made in SMA biomarker research in recent years.

    脊髓性肌萎缩生物标志物监测

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    遗传性痉挛性截瘫4型的研究进展

    王杰刘雅贤张丽春赵立荣...
    113-119页
    查看更多>>摘要：痉挛性截瘫4型(SPG4)是常染色体遗传性痉挛截瘫疾病中最常见的类型，主要临床特征为典型的单纯型遗传性痉挛性截瘫，神经功能损害仅限于下肢痉挛无力、高渗性膀胱障碍和下肢振动觉轻度减弱，不伴随出现神经萎缩、共济失调、认知障碍、癫痫发作和肌张力障碍等特征。SPAST是引起SPG4的主要致病基因，现已发现多种不同的SPAST致病变异体。该疾病存在高度临床异质性，相同致病变异体在不同患者间甚至在同一家系间也可表现出发病年龄与严重程度的差异。关于SPG4基因型和表型的相关性缺乏系统的研究，致病机制目前尚存在争议。本文对该疾病的临床特征、致病基因特点、基因型与表型的相关性、致病机理等进行了综述，以期为该疾病的临床诊疗提供参考。 Spastic paraplegia type 4 (SPG4) is the most common type of autosomally inherited spastic paraplegia. Its main clinical features include typical simple hereditary spastic paraplegia, with neurological impairments limited to lower limb spasticity, hypertonic bladder dysfunction, and mild weakening of lower limb vibration sensation, without accompanying features such as nerve atrophy, ataxia, cognitive impairment, seizures, and muscle tone disorders. SPAST is the main pathogenic gene underlying SPG4, and various pathogenic SPAST variants have been discovered. This disease has featured a high degree of clinical heterogeneity, and the same pathogenic variant can have different age of onset and severity among patients and even within the same family. There is a lack of systematic research on the correlation between the genotype and phenotype of SPG4, and the pathogenic mechanism has remained controversial. This article has provided a review for the clinical characteristics, pathogenic gene characteristics, correlation between the genotype and phenotype, and pathogenic mechanism of this disease, with an aim to provide reference for its clinical diagnosis and treatment.

    神经退行性疾病痉挛性截瘫4型SPAST基因临床异质性

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