一例Smith-Magenis患儿的遗传学诊断与分析

目的 对1例发育迟缓患儿进行遗传学诊断、分析,为临床咨询提供依据.方法 采用常规G显带分析患儿及其父母的外周血染色体核型,利用微阵列比较基因组杂交(aCGH)技术对患儿及其父母外周血进行检测.对检出的拷贝数变异(CNV)致病性采用美国医学遗传学与基因组学学会(ACMG)评分标准进行分类,对患儿基因型与表型关系进行分析....     

一例主动脉狭窄伴拇指缺如患儿的遗传学诊断CSCD

目的分析1例主动脉狭窄伴拇指缺如患儿的发病机制,为遗传咨询提供依据。方法用常规G显带分析患儿及其父母的外周血染色体核型,用微阵列比较基因组杂交（array comparative genomic hybridization,aCGH）技术对患儿及其父母进行染色体片段重复／缺失的分析。结果G显带分析结果显示患儿及其父母染色体核型未见异常。aCGH检测结果显示患儿2q22．3-q23．3区存在5．86Mb的杂合缺失,其父母未检测到染色体微重复／微缺失。结论患儿2q22．3-q23．3缺失为新发突变,诊断为2q23．1微缺失综合征,MBD5基因可能是该综合征的关键基因。     

微阵列比较基因组杂交技术分析一例猫叫综合征患儿的基因组拷贝数变异

目的 对1例猫叫综合征患儿进行基因组拷贝数分析,寻找其致病原因.方法 对患儿外周血进行常规G显带分析,应用微阵列比较基因组杂交技术进行全基因组扫描,并应用荧光原位杂交技术对异常拷贝数区域进行验证.结果 患儿染色体核型为46,XY,der(5)(p?).微阵列比较基因组杂交显示其在5p14.2-p15.3处存在23.263Mb的片段缺失,12号染色体12p31区域存在14.602 Mb的片段重复.重复片段连接至5p14.2处,形成5号衍生染色体,即arr cgh 5p15.3p14.2(PLEKHG4B→CDH12)×1 pat,12p13.33p13.1(IQSEC3→GUC Y2C)× 3 pat.荧光原位杂交证实患儿存在5p末端缺失及12p末端重复.结论 5号染色体不平衡易位导致患儿5p末端缺失可能是患儿的病因.微阵列比较基因组杂交技术具有高分辨、高通量和高准确性的优点,适用于全基因组拷贝变异分析.     

一例Williams-Beuren综合征患儿的遗传学诊断与分析

目的对1例疑似Williams-Beuren综合征的先天性心脏病患儿进行遗传学诊断,分析其可能的分子病因,为临床遗传咨询提供依据。方法用常规G-显带分析了患儿及其双亲的外周血染色体核型,并用微阵列比较基因组杂交(array comparative genomic hybridization,aCGH)技术检测患儿及其双亲可能存在的染色体微重复/微缺失异常。结果G-显带分析结果显示,未见患儿及其父母外周血染色体核型的异常。aCGH检测结果发现,患儿第7号染色体的7q11.23区存在1个1.41 Mb长度的杂合性缺失,而其双亲不存在此染色体微缺失异常。结论患儿的7q11.23杂合性缺失为新发突变(de novo mutation),可确诊为Williams-Beuren综合征。     

智力障碍和小头畸形伴脑桥和小脑发育不全患儿2例的临床及遗传学分析

目的探讨2例智力障碍和小头畸形伴脑桥和小脑发育不全(MICPCH)患儿的临床特征与遗传学病因。方法选取2019年4月至2021年12月期间于河南省人民医院就诊的2例MICPCH患儿为研究对象。收集患儿的临床资料, 采集患儿及其父母的外周静脉血样和患儿1母亲的羊水样本, 用全外显子组测序(WES)、微阵列比较基因组杂交(aCGH)与荧光定量PCR(qPCR)对2例患儿及其父母、患儿1母亲的胎儿进行检测, 对候选变异进行致病性分析。结果患儿1为6岁女性, 主要临床表现为运动与语言发育迟缓;患儿2为4岁半女性, 主要临床表现为小头畸形与智力低下。WES检测结果显示患儿2的CASK基因第4 ～ 14外显子区域(chrX:41446160₄1604854)存在158.7 kb重复, 其父母均未见该变异, 提示为新发变异;aCGH检测结果显示患儿1的CASK基因第3外显子区域(chrX: 41637892₄1666665)存在29 kb缺失, 其父母和母亲的胎儿均未见该变异, 提示为新发变异;qPCR检测结果进一步证实了WES与aCGH的检测结果。CAS...     

一个先天性主动脉瓣上狭窄家系的分子遗传性分析

目的 检测一个临床诊断为先天性升主动脉狭窄家系患者的基因组拷贝数变异,明确其发病的遗传学基础.方法 以一个先天性升主动脉狭窄家系为研究对象,收集患儿及其患病父亲、正常母亲外周血标本,常规提取基因组DNA.应用Affymetrix人类全基因组SNP 6.0芯片对患儿及1例正常健康对照个体进行检测,应用实时定量PCR(real-time quantitative polymerase-chain-reaction,qPCR)方法对芯片分析结果进行验证.结果 经Affymetrix SNP 6.0 芯片分析显示患儿染色体7q11.23区域内弹力蛋白基因(elastin,ELN)5′端大部分及基因上游区域共约80 kb发生杂合性缺失.在ELN基因内设计4对qPCR引物,在家系内进行验证,结果显示ELN的缺失向下游至少累及至第22外显子,且患儿父亲携带与患儿相同的杂合性缺失.结论 ELN 基因部分杂合性缺失为该患儿及其父亲发病的原因,二者之先天异常为主动脉瓣上狭窄(supravalvular aortic stenosis,SVAS).

Abstract：

Objective To detect the copy number variations(CNVs)in a family with congenital narrowing of the ascending aorta,and to explore the underlying genetic causes of the disease.Methods Peripheral blood samples were collected from an affected boy,his affected father and his apparently normal mother.Genomic DNA Was extracted and genotyped using Affymetrix Genome-Wide Human SNP Array 6.0.CNVs were confirmed by real-time quantitative PCR(qPCR).Results Our SNP Array 6.0analysis showed in the boy an about 80kb heterozygous deletion affecting part of the elastin gene(ELN).Further qPCR assays for four confirmed the presence of the deletion in the boy and his father,and indieated that the deletion involved at least the first 22 ELN exons.Conclusion A heterozygous deletion affecting part of the ELN gene has been identified in the boy and his father, A diagnosis of supravalvular aortic stenosis(SVAS)could he made based on the molecular finding.     

微阵列比较基因组杂交技术诊断9p部分三体患儿一例

目的 确定1例生长发育迟缓、语言发育障碍患儿的核型,分析其染色体畸变与表型的相关性,探讨微阵列比较基因组杂交(array-based comparative genomic hybridization,array-CGH)在临床分子遗传学诊断中的应用及其优越性.方法 应用G显带对患儿及其父母进行核型分析,进一步采用array-CGH技术对患儿进行全基因组高分辨率扫描分析,确定其衍生染色体片段的来源.结果 G显带染色体分析显示患儿及其母亲均为inv(9)(p13q13)携带者,患儿13号染色体存在一衍生片段.array-CGH结果证实患儿衍生片段源自9号染色体短臂,确定为9p13.1-p24.3三体.患儿母亲array-CGH结果未见异常.结论 inv(9)(p13q13)与患儿异常表型无关,患儿的异常表型可归因于9p13.1-p24.3三体.同传统细胞遗传分析方法相比,array-CGH具有高分辨率和高精确性的优点.     

三例Kleefstra综合征患儿临床和遗传学分析

目的对3例不明原因的发育迟缓(developmental delay, DD)/智力障碍(intellectual disability, ID)患儿进行临床症状和染色体微阵列分析(chromosome microarray analysis, CMA), 明确其可能的病因。方法采集3例DD/ID患儿的外周静脉血样, 进行CMA检测。结果例1的9号染色体q34.3区段约有190 kb的DNA片段缺失, 包含Kleefstra综合征(OMIM 610253)的关键基因EHMT1(OMIM 607001)的大部分区域;例2和例3为同胞姐妹, CMA检测显示均存在相同的4处染色体片段异常, 其中9号染色体q34.3区域缺失长度分别是154 kb和149 kb, 均包含EHMT1和CACNA1B(OMIM 601012)基因, 其余变异无临床意义。结论 3例患儿的染色体9q34.3微缺失可能是其DD/ID的致病原因, EHMT1是关键基因。     

微阵列比较基因组杂交分析一例足月小样儿的染色体畸变

目的 分析一例足月小样儿的染色体畸变,探讨患儿低出生体重的原因.方法 采集临床已确诊的足月小样儿外周血并抽提基因组DNA,进行微阵列比较基因组杂交,分析患儿基因组拷贝数的改变.培养患儿及其父母外周血淋巴细胞,进行染色体核型分析并确定患儿染色体畸变的来源.结果 微阵列比较基因组杂交显示患儿在10q125.2→qter区域存在长22 Mb片段的重复,同时在15q26.2→qter区域存在长5 Mb片段的缺失.核型分析显示患儿核型为46,XY,-15,+der(15)t(10;15)(q25;q26)pat.结论 患儿在10q25.2→qter区域存在部分三体,而在15q26.2→qter区域存在部分单体,这两种染色体畸变可能均是导致患儿表现为足月小样儿的病因之一.     

光谱核型分析联合微阵列比较基因组杂交诊断15号环状染色体综合征

目的 探讨联合应用光谱核型分析技术(spectral karyotyping,SKY)和微阵列比较基因组杂交技术(microarray-based comparative genomic hybridization,array-CGH)在诊断复杂疑难的环状染色体畸变中的价值.方法 对1例常规G显带染色体核型分析疑诊为46,XY,r(15)?的8岁男性生长发育迟缓患儿依次应用SKY及array-CGH技术常规进行制片杂交,并通过相应的显微摄像系统和计算机软件分析结果.结果 SKY技术明确了该患儿环状染色体来源于15号染色体,array-CGH技术明确患儿15q26.3末端存在约594 kb的缺失,染色体基因位点编码范围为99689349-100282878.结论 联合应用现代分子细胞遗传学技术可以从细胞到分子水平精确诊断复杂疑难的环状染色体病例,是常规染色体核型分析的有益补充,也有利于细胞遗传学向分子水平深入.     

Novel ELN mutation in a family with supravalvular aortic stenosis and intracranial aneurysm

Pathogenic germline mutations in ELN can be detected in patients with supravalvular aortic stenosis. The mutation might occur de novo or be inherited following an autosomal dominant pattern of inheritance. In this report we describe a three-generation family suffering from supravalvular aortic stenosis, various other arterial stenoses, sudden death, and intracranial aneurysms. A frameshift mutation in exon 12, not described before, was detected in the affected family members. This report emphasises the importance of family history, genetic counselling, and demonstrates the great variability in the phenotype within a single SVAS family.     

一例合并6q21-q22．31微缺失的锁骨颅骨发育不良患者的遗传学分析CSCD

目的对1例发育迟缓伴多发畸形患儿进行遗传学检测,分析其预后及发生机制,为临床咨询提供依据。 方法采用常规G显带和微阵列比较基因组杂交（array comparative genomic hybridization, aCGH）技术分析患儿及其父母的外周血染色体核型和DNA。结果G显带分析结果显示,患儿染色体核型为46,XX,del（6）（q22）,inv（6）（p21.1q21）,其父母染色体核型未见异常。aCGH检测结果显示患儿6p21.1区存在800 kb杂合缺失,包含RUNX2基因,6q21-q22.31区存在11.79 Mb杂合缺失,其父母未检测到染色体微重复/微缺失。 结论患儿为染色体新发倒位,两处微缺失均为新发突变,具有致病性。6p21.1区域RUNX2基因微缺失导致锁骨颅骨发育不良,6q21-q22.31区域微缺失可能与患儿脑部结构发育异常相关。     

Supravalvular aortic stenosis cosegregates with a familial 6;7 translocation which disrupts the elastin gene

Supravalvular aortic stenosis (SVAS) is an autosomal dominant disorder characterized by abnormalities of development of the great vessels. SVAS is also commonly part of Williams syndrome. Linkage to the elastin gene on chromosome 7q11 has recently been reported in two kindreds with SVAS. Previous reports of patients with 7q11 deletions have noted great vessel abnormalities in some. We report on a family in which SVAS is cosegregating with a balanced reciprocal translocation, t(6:7) (p21.1;q11.23), providing further evidence that SVAS is the result of mutation of elestin at 7q11.23 region. The propositus of the translocation family has some minor anomalies which occur in Williams syndrome, Suggesting that elestin abnormalities may cause some of the abnormalities found in Williams syndrome. © 1993 Wiley-Liss, Inc. © 1993 Wiley-Liss, Inc.     

Three decades of follow-up of aortic and pulmonary vascular lesions in the Williams-Beuren syndrome

The diagnostic criteria of the Williams-Beuren syndrome (WBS) were established almost 3 decades ago. Until now there has been little knowledge about the natural and post-surgical history of vascular lesions in this syndrome. In order to evaluate the long term follow-up of aortic and pulmonary vascular lesions, we have analysed the catheterization data, angiocardiograms, and Doppler-echo measurements in 59 patients who were seen at least twice in our institution between 1961 and 1993. Their follow-up periods ranged from 2.1 to 28.2 years. Of 45 patients with supravalvular aortic stenosis (SVAS) with a mean follow-up period of 12.9 years, it became evident that pressure gradients of less than 20 mm Hg in infancy generally remained unchanged during the first two decades of life. Pressure gradients exceeding 20 mm Hg increased from an average of 35.5 mm Hg to 52.7 mm Hg in 13 patients. Of these, 8 required surgical relief of the narrowing. In 7 patients aortic hypoplasia was documented. In 5 of them the caliber of the aorta showed a tendency towards normalisation within a period of 11.9 to 23.9 years. Of 6 individuals with aortic hypoplasia and surgical relief of SVAS, 4 patients developed restenosis at the distal end of the aortoplasty patch. In contrast, 9 patients with operated SVAS—but without aortic hypoplasia—remained free of restenosis over a period of 11 years (mean). Coarctation occurred in 4/59 patients; restenosis was seen in 2 after 5 and 16 years. Peripheral pulmonary stenosis was followed in 23 patients over 14.4 years (mean). During this period the systolic pressure gradients fell from 23 to 9.3 mm Hg (mean). In adolescence and adulthood the gradients were below 20 mm Hg in 22/23 individuals. In WBS there is a good long-term prognosis for SVAS if gradients during infancy are low. SVAS with gradients above 20 mm Hg tend to increase; 60% of them require surgical relief with good long-term results. But aortic hypoplasia impairs the prognosis of operated SVAS, because restenosis may occur. Peripheral pulmonary stenosis generally shows a good long-term prognosis. © 1994 Wiley-Liss, Inc.     

Concurrence of supravalvular aortic stenosis and peripheral pulmonary stenosis in three generations of a family: A form of arterial dysplasia

Isolated supravalvular aortic stenosis (SVAS) commonly is an autosomal dominant trait; it may also occur in the Williams syndrome (WS). While peripheral pulmonary stenosis (PPS) can occur in the same individual with familial isolated SVAS, concurrence of these lesions in different relatives of a family is uncommon. We describe five affected individuals in one family; three had isolated SVAS, one had isolated PPS, and one had SVAS and PPS. Based on this family and review of literature, we suggest that SVAS is a form of arterial dysplasia encompassing PPS in its spectrum. It is developmentally distinct from other left heart obstructive lesions that are hypothesized to be related to blood flow abnormalities in the developing embryo. We also conclude that the clinical disorder in this family represents one that is distinct from WS. © 1993 Wiley-Liss, Inc.     

Calcific aortic valve stenosis: Immunohistochemical analysis of inflammatory infiltrate

Calcific aortic valve disease is considered a form of atherosclerosis and, like the latter, possibly of inflammatory origin. The aim of our work was to study the pattern of cellular infiltrate in calcific aortic valve stenosis (CAS). Fifteen operatively excised calcified aortic valves were examined by histology and immunohistochemistry (CD20, CD79α, CD3, CD4, CD8, CD68, CD138, CD117, BJK, BJL, IgA, IgD, IgG, IgG4 and IgM). The findings revealed that in CAS, there were chronic inflammatory features with infiltrates comprising lymphocytes, polyclonal plasma cells, histiocytes and mast cells. In T-lymphocytes, CD4 prevailed over CD8. In B-lymphocytes, there was a slight preponderance of CD20 over CD79α. The BJL (lambda)-positive plasma cells prevailed over the BJK (kappa) ones. The CD138-positive plasma cells comprised 24% IgA-, 20% IgD-, 41% IgG- (including 11% of IgG4-) and 15% IgM-positive cells. CAS did not fulfill the criteria of the recently described clinicopathological entity IgG4-related sclerosing systemic disease. The inflammatory process was the same in both subsets of CAS - those with trileaflet (normally formed) valves and those with congenitally bicuspid valves.     

Microarray comparative genomic hybridization analysis of 59 patients with schizophrenia

Schizophrenia is a common psychiatric disorder with a strong genetic contribution. Disease-associated chromosomal abnormalities in this condition may provide important clues, such as DISC1. In this study, 59 schizophrenia patients were analyzed by microarray comparative genomic hybridization (CGH) using custom bacterial artificial chromosome (BAC) microarray (4,219 BACs with 0.7-Mb resolution). Chromosomal abnormalities were found in six patients (10%): 46,XY,der(13)t(12;13)(p12.1; p11).ish del(5)(p11p12); 46,XY, ish del(17)(p12p12); 46,XX.ish dup(11)(p13p13); and 46,X,idic(Y)(q11.2); and in two cases, mos 45,X/46XX. Autosomal abnormalities in three cases are likely to be pathogenic, and sex chromosome abnormalities in three follow previous findings. It is noteworthy that 10% of patients with schizophrenia have (sub)microscopic chromosomal abnormalities, indicating that genome-wide copy number survey should be considered in genetic studies of schizophrenia.     

Sotos综合征患儿的遗传学分析

目的对1例智力低下患儿进行遗传学分析,明确患儿的遗传学病因。方法对1例智力低下患儿行G显带染色体核型分析、单核昔酸多态性微阵列(single nucleotide polymorphism array,SNParray)及荧光原位杂交(fluorescence in situ hybridization,FISH)检测,患儿父母行外周血染色体核型及FISH分析。结果SNP-array分析显示患儿染色体5q35.2q35.3存在5077 kb缺失,7q36.2q36.3存在4964 kb重复,FISH验证了SNP-array的结果。根据患儿SNP-array和FISH结果及其父母外周血FISH结果,确认胎儿父亲为隐匿性t(5;7)(q35.2;q36.2)携带者,而胎儿遗传了其中一条衍生的5号染色体der(5)t(5)7)(q35.2;q3&2)。结论5q35.2q35.3微缺失对Sotos综合征表型的产生起主导作用,SNParray结合FISH技术有助于发现染色体隐匿性易位。