背景:Silver-Russell综合征(SRS)是一种临床和遗传异质性疾病,其特征是严重的宫内发育迟缓,出生后生长不良,特征性的面部特征,身体不对称。染色体11p15.5印迹基因簇的印迹基因的低甲基化和染色体7(mUPD7)的母体单亲二体性是主要的表观遗传障碍。这项研究的目的是表征表观基因型,基因型,和这些患者在台湾的表型。
方法:两百六位临床疑似SRS患者被转诊进行诊断测试,通过使用甲基化特异性多重连接依赖性探针扩增和甲基化特异性聚合酶链反应测定的高分辨率解链分析,对H19相关印迹中心(IC)1和印迹PEG1/MEST区的甲基化进行分析。我们还应用了全基因组策略来检测拷贝数变化和杂合性丢失。根据Bartholdi等人提出的SRS评分系统记录并分析临床表现。结果:在206名转诊受试者中,100人被分类为具有SRS的临床诊断(评分≥8,最大=15),106人的SRS评分≤7。在临床诊断为SRS的受试者中,有45%(45/100)检测到分子病变,而SRS评分≤7的患者为5%(5/106)。37名受试者有IC1低甲基化,10名受试者有mUPD7,3名受试者有微缺失.发现“IC1低甲基化”和“mUPD7”组之间的一些临床特征具有统计学差异(p<0.05),包括出生时的相对大头畸形(89%vs.50%),三角形脸(89%与50%),第五指的弯曲(68%vs.20%),和SRS评分(11.4±2.2vs.8.3±2.5)。
结论:SRS评分与分子诊断率呈正相关(p<0.001)。mUPD7的SRS受试者似乎比IC1低甲基化者具有更少的典型特征和更低的SRS得分。仔细的临床观察和及时的分子确认对于这些患者的早期诊断和多学科管理很重要。
BACKGROUND: Silver-Russell syndrome (SRS) is a clinically and genetically heterogeneous disorder characterized by severe intrauterine growth retardation, poor postnatal growth, characteristic facial features, and body asymmetry. Hypomethylation of the imprinted genes of the chromosome 11p15.5 imprinting gene cluster and maternal uniparental disomy of chromosome 7 (mUPD7) are the major epigenetic disturbances. The aim of this study was to characterize the epigenotype, genotype, and phenotype of these patients in Taiwan.
METHODS: Two hundred and six subjects with clinically suspected SRS were referred for diagnostic testing, which was performed by profiling the methylation of H19-associated imprinting center (IC) 1 and the imprinted PEG1/MEST region using methylation-specific multiplex ligation-dependent probe amplification and high-resolution melting analysis with a methylation-specific polymerase chain reaction assay. We also applied a whole genome strategy to detect copy number changes and loss of heterozygosity. Clinical manifestations were recorded and analyzed according to the SRS scoring system proposed by Bartholdi et al. Results: Among the 206 referred subjects, 100 were classified as having a clinical diagnosis of SRS (score ≥ 8, maximum = 15) and 106 had an SRS score ≤ 7. Molecular lesions were detected in 45% (45/100) of the subjects with a clinical diagnosis of SRS, compared to 5% (5/106) of those with an SRS score ≤ 7. Thirty-seven subjects had IC1 hypomethylation, ten subjects had mUPD7, and three subjects had microdeletions. Several clinical features were found to be statistically different (p < 0.05) between the \"IC1 hypomethylation\" and \"mUPD7\" groups, including relative macrocephaly at birth (89% vs. 50%), triangular shaped face (89% vs. 50%), clinodactyly of the fifth finger (68% vs. 20%), and SRS score (11.4 ± 2.2 vs. 8.3 ± 2.5).
CONCLUSIONS: The SRS score was positively correlated with the molecular diagnosis rate (p < 0.001). The SRS subjects with mUPD7 seemed to have fewer typical features and lower SRS scores than those with IC1 hypomethylation. Careful clinical observation and timely molecular confirmation are important to allow for an early diagnosis and multidisciplinary management of these patients.