Goldenhar综合征家系收集、表型分析和遗传学研究
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摘要
目的：分析Goldenhar综合征的表型为该病的临床诊断提供依据；收集Goldenhar患者的遗传资料,为揭示此类疾病的遗传基础及发生机制奠定基础。
方法：分析69例Goldenhar综合征患者的临床资料及表型间的相关性。采集一Goldenhar综合征家系的全部成员及4组核心家系成员的的新鲜血液,试剂盒提取全基因组DNA。
结果：69例患者中,绝大多数为散发(91.3%),男女患病机会均等；双侧受累39例(56.5%),单侧受累30例(43.5%,左14：右16)；耳前赘(88.4%)、眼球皮样瘤(84.1%)和其它眼异常(52.2%)是主要症状,半侧颜面短小与口面裂、颌发育不良、除耳廓畸形及耳前赘外的其它耳异常呈正相关(p<0.05),智力障碍与脑发育不良、视力减退、语言障碍、除耳廓畸形及耳前赘外的其它耳异常成明显正相关(p<0.01)。收集到一Goldenhar综合征家系内的4例患者及11例正常家系成员和4例散发患者及其父母的高质量DNA样本。
结论：Goldenhar综合征表型复杂多样,属于相关发育领域的表型常伴发出现；双侧受累的患者往往症状更严重,累及更多器官系统的发育不良,需要接受更详细的临床检查。收集了一Goldenhar综合征家系及4组父母-患者核心家系的DNA,是国内宝贵的遗传资源,为揭示此类疾病的遗传基础及发生机制奠定了良好的基础。
目的：为探索Goldenhar综合征的致病原因,筛查8例患者的SALL1和TCOF1基因突变情况。
方法：取8例患者及其父母和正常同胞的基因组DNA,PCR扩增SALL1和TCOF1的全部外显子及部分内含子,用直接双向测序、Blast比对进行突变分析。
结果：在SALL1基因中发现2个多态数据库已报道的单核苷酸多态；在TCOF1基因中发现了7个序列变异,其中6个已被报道为多态,1个为新发现的内含子突变。所有序列变异都存在于患者的正常亲属中,与疾病表型无共分离现象。
结论：未发现此8例患者在SALL1和TCOF1基因中的致病性突变,支持Goldenhar综合征在遗传基础上是有别于TBS和TCS的一种独立疾病。
目的：分析Goldenhar综合征患者的基因组拷贝数变异,寻找与该疾病相关的位点。
方法：采用Human CNV370-Quadv3-0芯片对家系成员及4组父母-患者核心家系进行拷贝数变异(Copy Number Variation,CNV)的基因分型研究,芯片扫描结果用BeadStudio软件进行CNV分析,并对一个可能与患者表型相关的新发拷贝数变异进行real-time PCR验证。
结果：CNV分析在三个散发患者中发现10个新发的拷贝数变异,综合考虑DGV数据库、27个正常对照样本以及CNV区域的基因信息情况,推测其中分别位于5q13.2、1q31.1和8p23.1区域的CNV可能与对应患者的表型相关,并用real-time PCR证实了5q13.2区域内的CNV在患者GS1中的存在。家系内CNV分析发现153个CNVs,但患者和正常个体间在CNVs数量和大小方面都没有明显差异,未发现与患者表型相关的CNV。
结论：通过CNV分析,发现位于5q13.2的单拷贝缺失、1q31.1的重复和8p23.1的单拷贝缺失可能分别与对应患者的表型相关。在一Goldenhar综合征家系的全基因组扫描数据中,没有发现与患者表型共分离的拷贝数突变,可能即使在同一家族内,其病因也是非常复杂的,要阐明此类疾病的遗传基础将是一个非常具有挑战性的任务。
Objective To analyze the clinical phenotype and apply the referenced diagnose for Goldenhar syndrome; To collect the genetic resourse of Goldenhar syndrome for providing us with the information to explore etiological factors for this disorder.
Methods A series of 69 patients with Goldenhar syndrome were retrospectively reviewed, and Pearson's correlation analysis were performed. and their unaffected parents were collected with genome DNA. Genomic DNA was extracted from peripheral blood samples of the members of a family with Goldenahr syndrome and another four family Trios (father, mother and patient) using a genomic DNA purification kit.
Results Of the 69 patients with Goldenhar syndrome, Most cases (91.3%) were sporadic, and 34 patients were male and 35 patients were female, Bilateral involvement was present in 39 cases (56.5%), whereas 30 cases (43.5%,14 showed on the left side and 16 on the right side) were unilateral affected. Preauricular tag (88.4%), epibulbar dermoids (84.1%) and other anomalies of the eyes (52.2%) were mail clinical signs, and hemifacial microsomia correlated with orofacial cleft, dysplasia of maxilla and/or mandible, and anomalies of the ears, other than malformed auricle and preauricular tag (p<0.05). Dysnoesia clustered with brain anomalies, visual deterioration, delay of speech development, and anomalies of the ears, other than malformed auricle and preauricular tag (p<0.01). A family with 5 Goldenhar syndrome patients and the Trios families of 4 sporadic cases were collected with genomic DNA.
Conclusion Goldenhar syndrome is a complex condition and shows variable phenotypes, and some clinical signs belonging to the associated developmental fields often appeared together. Patients with bilateral involvement often suffered more developmental abnormalities and required more careful examinations. The genetic resource of one family with Goldenhar syndrome and another 4 Trios families were collected for providing us with the information to reveal the aetiology mechanism of this disorder.
Objective Mutation screen of SALL1 and TCOF1 in eight patients with Goldenhar syndrome to explore the pathogenic cause of this complex disorder.
Methods eight patients and their unaffected relatives were collected with clinical data and genome DNA. All the exons and some of the introns of SALL1 and TCOF1 were amplified by polymerase chain reaction (PCR) and the PCR products were subjected to autotic DNA sequencing.
Results Two polymorphic sites in SALL1 and seven variants in TCOF1 were detected, and all the variants also presented in the unaffected individuals, showing no mutation segregating with the disease.
Conclusion Pathogenic mutation of SALL1 and TCOF1 were excluded in these patients, supporting that Goldenhar syndrome is a specific entity.
Objective Investigate the copy number variations (CNVs) in a family with Goldenhar syndrome and four sporadic patients to identify possible susceptibility locus.
Methods Genomic DNA of 13 family members and 4 family Trios(father, mother and patient) was genotyped with Illumina Human 370 Genotyping BeadChip. Results were analyzed using Beadstudio software to identify CNVs. Then, one de novo CNV region which may be associated with the disorder was validated by real-time PCR.
Results Ten de novo CNVs were identified in 3 sporadic patients. After analyzing the information of database of genomic variants (DGV), CNVs of 27 health controls and all the genes in the 10 CNV regions, three CNVs located on 5q13.2,1q31.1 and 8p23.1 may be considered to associate with Goldenhar syndrome. Then, the CNV on 5q13.2 was confirmed by real-time PCR. A total of 153 CNVs were identified in the family with 5 Goldenhar syndrome patients, but there were no significant differences of the CNV number (p=0.649, t-test) or CNV size (p=0.304, Wilcoxon Mann-Whitney test) between the affected and unaffected individuals, and no clear copy number variation was identified responsible for Goldenhar syndrome in this family.
Conclusion A microdeletion in 5q13.2, a microreplication in 1q31.1 and a microdeletion in 8p23.1 may be associated with Goldenhar syndrome. CNV analysis in the family identified no causative variant, indicating that a complex aetiology may be present even in a consanguineous family, which makes the ascertainment of the cause of Goldenhar syndrome challenging.
方法：分析69例Goldenhar综合征患者的临床资料及表型间的相关性。采集一Goldenhar综合征家系的全部成员及4组核心家系成员的的新鲜血液,试剂盒提取全基因组DNA。
结果：69例患者中,绝大多数为散发(91.3%),男女患病机会均等；双侧受累39例(56.5%),单侧受累30例(43.5%,左14：右16)；耳前赘(88.4%)、眼球皮样瘤(84.1%)和其它眼异常(52.2%)是主要症状,半侧颜面短小与口面裂、颌发育不良、除耳廓畸形及耳前赘外的其它耳异常呈正相关(p<0.05),智力障碍与脑发育不良、视力减退、语言障碍、除耳廓畸形及耳前赘外的其它耳异常成明显正相关(p<0.01)。收集到一Goldenhar综合征家系内的4例患者及11例正常家系成员和4例散发患者及其父母的高质量DNA样本。
结论：Goldenhar综合征表型复杂多样,属于相关发育领域的表型常伴发出现；双侧受累的患者往往症状更严重,累及更多器官系统的发育不良,需要接受更详细的临床检查。收集了一Goldenhar综合征家系及4组父母-患者核心家系的DNA,是国内宝贵的遗传资源,为揭示此类疾病的遗传基础及发生机制奠定了良好的基础。
目的：为探索Goldenhar综合征的致病原因,筛查8例患者的SALL1和TCOF1基因突变情况。
方法：取8例患者及其父母和正常同胞的基因组DNA,PCR扩增SALL1和TCOF1的全部外显子及部分内含子,用直接双向测序、Blast比对进行突变分析。
结果：在SALL1基因中发现2个多态数据库已报道的单核苷酸多态；在TCOF1基因中发现了7个序列变异,其中6个已被报道为多态,1个为新发现的内含子突变。所有序列变异都存在于患者的正常亲属中,与疾病表型无共分离现象。
结论：未发现此8例患者在SALL1和TCOF1基因中的致病性突变,支持Goldenhar综合征在遗传基础上是有别于TBS和TCS的一种独立疾病。
目的：分析Goldenhar综合征患者的基因组拷贝数变异,寻找与该疾病相关的位点。
方法：采用Human CNV370-Quadv3-0芯片对家系成员及4组父母-患者核心家系进行拷贝数变异(Copy Number Variation,CNV)的基因分型研究,芯片扫描结果用BeadStudio软件进行CNV分析,并对一个可能与患者表型相关的新发拷贝数变异进行real-time PCR验证。
结果：CNV分析在三个散发患者中发现10个新发的拷贝数变异,综合考虑DGV数据库、27个正常对照样本以及CNV区域的基因信息情况,推测其中分别位于5q13.2、1q31.1和8p23.1区域的CNV可能与对应患者的表型相关,并用real-time PCR证实了5q13.2区域内的CNV在患者GS1中的存在。家系内CNV分析发现153个CNVs,但患者和正常个体间在CNVs数量和大小方面都没有明显差异,未发现与患者表型相关的CNV。
结论：通过CNV分析,发现位于5q13.2的单拷贝缺失、1q31.1的重复和8p23.1的单拷贝缺失可能分别与对应患者的表型相关。在一Goldenhar综合征家系的全基因组扫描数据中,没有发现与患者表型共分离的拷贝数突变,可能即使在同一家族内,其病因也是非常复杂的,要阐明此类疾病的遗传基础将是一个非常具有挑战性的任务。
Objective To analyze the clinical phenotype and apply the referenced diagnose for Goldenhar syndrome; To collect the genetic resourse of Goldenhar syndrome for providing us with the information to explore etiological factors for this disorder.
Methods A series of 69 patients with Goldenhar syndrome were retrospectively reviewed, and Pearson's correlation analysis were performed. and their unaffected parents were collected with genome DNA. Genomic DNA was extracted from peripheral blood samples of the members of a family with Goldenahr syndrome and another four family Trios (father, mother and patient) using a genomic DNA purification kit.
Results Of the 69 patients with Goldenhar syndrome, Most cases (91.3%) were sporadic, and 34 patients were male and 35 patients were female, Bilateral involvement was present in 39 cases (56.5%), whereas 30 cases (43.5%,14 showed on the left side and 16 on the right side) were unilateral affected. Preauricular tag (88.4%), epibulbar dermoids (84.1%) and other anomalies of the eyes (52.2%) were mail clinical signs, and hemifacial microsomia correlated with orofacial cleft, dysplasia of maxilla and/or mandible, and anomalies of the ears, other than malformed auricle and preauricular tag (p<0.05). Dysnoesia clustered with brain anomalies, visual deterioration, delay of speech development, and anomalies of the ears, other than malformed auricle and preauricular tag (p<0.01). A family with 5 Goldenhar syndrome patients and the Trios families of 4 sporadic cases were collected with genomic DNA.
Conclusion Goldenhar syndrome is a complex condition and shows variable phenotypes, and some clinical signs belonging to the associated developmental fields often appeared together. Patients with bilateral involvement often suffered more developmental abnormalities and required more careful examinations. The genetic resource of one family with Goldenhar syndrome and another 4 Trios families were collected for providing us with the information to reveal the aetiology mechanism of this disorder.
Objective Mutation screen of SALL1 and TCOF1 in eight patients with Goldenhar syndrome to explore the pathogenic cause of this complex disorder.
Methods eight patients and their unaffected relatives were collected with clinical data and genome DNA. All the exons and some of the introns of SALL1 and TCOF1 were amplified by polymerase chain reaction (PCR) and the PCR products were subjected to autotic DNA sequencing.
Results Two polymorphic sites in SALL1 and seven variants in TCOF1 were detected, and all the variants also presented in the unaffected individuals, showing no mutation segregating with the disease.
Conclusion Pathogenic mutation of SALL1 and TCOF1 were excluded in these patients, supporting that Goldenhar syndrome is a specific entity.
Objective Investigate the copy number variations (CNVs) in a family with Goldenhar syndrome and four sporadic patients to identify possible susceptibility locus.
Methods Genomic DNA of 13 family members and 4 family Trios(father, mother and patient) was genotyped with Illumina Human 370 Genotyping BeadChip. Results were analyzed using Beadstudio software to identify CNVs. Then, one de novo CNV region which may be associated with the disorder was validated by real-time PCR.
Results Ten de novo CNVs were identified in 3 sporadic patients. After analyzing the information of database of genomic variants (DGV), CNVs of 27 health controls and all the genes in the 10 CNV regions, three CNVs located on 5q13.2,1q31.1 and 8p23.1 may be considered to associate with Goldenhar syndrome. Then, the CNV on 5q13.2 was confirmed by real-time PCR. A total of 153 CNVs were identified in the family with 5 Goldenhar syndrome patients, but there were no significant differences of the CNV number (p=0.649, t-test) or CNV size (p=0.304, Wilcoxon Mann-Whitney test) between the affected and unaffected individuals, and no clear copy number variation was identified responsible for Goldenhar syndrome in this family.
Conclusion A microdeletion in 5q13.2, a microreplication in 1q31.1 and a microdeletion in 8p23.1 may be associated with Goldenhar syndrome. CNV analysis in the family identified no causative variant, indicating that a complex aetiology may be present even in a consanguineous family, which makes the ascertainment of the cause of Goldenhar syndrome challenging.
引文
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