Genetic heterogeneity of patients with suspected Silver-Russell syndrome: genome-wide copy number analysis in 82 patients without imprinting defects.
Genetic heterogeneity of patients with suspected Silver-Russell syndrome: genome-wide copy number analysis in 82 patients without imprinting defects.
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DOI：
10.1186/s13148-017-0350-6
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发表时间：
2017
影响因子：
5.7
通讯作者：
Kagami M
中科院分区：
文献类型：
--
作者：
Inoue T;Nakamura A;Fuke T;Yamazawa K;Sano S;Matsubara K;Mizuno S;Matsukura Y;Harashima C;Hasegawa T;Nakajima H;Tsumura K;Kizaki Z;Oka A;Ogata T;Fukami M;Kagami M
Silver-Russell综合征(SRS)是一种罕见的先天性疾病，以出生前和出生后发育障碍和畸形为特征。最近，除了H19差异甲基化区域(DMR)的低甲基化和母体单亲染色体7号染色体的低甲基化外，已有报道在SRS表型患者中发现了致病拷贝数变异(PCNV)和印记缺陷。本研究旨在阐明PCNV引起的SRS表型患者的频率和临床特征。我们使用目录阵列对符合Netchine-Harbison临床评分系统(NH-CS)(SRS-Compatible)的54名患者和28名患者进行了阵列比较基因组杂交分析，其中28名患者有三个NH-CS项目，并伴有三角脸和/或五指斜指和/或短指(SRS-like)，9个DMR的甲基化水平与已知印迹疾病无关。然后我们调查了PCNV患者的临床特征。54例SRS相合的患者中有3例(5.6%)和28例SRS样患者中的2例(7.1%)有PCNVS。在SRS相容的患者中，在4p16.3、镶嵌三体18、19q13.11-12、7q11.23、7q11.23、7q11.23、19q13.11-12、1.41-1.97Mb分别检测到3.5kMb缺失、嵌合三体18、3.77-4.00mb缺失。在两名患者中发现了先天性心脏病(CHDS)，在四名患者中观察到了中度到严重的全身性发育延迟。在我们研究的患者中，5.6%的SRS相容患者和7.1%的SRS样患者有PCNV。所有PCNV都被报道为邻近缺失综合征或马赛克18三体的遗传原因。我们的研究表明，具有类似SRS表型的PCNV患者表现出较高的CHD倾向和/或明显的发育迟缓。
Silver-Russell syndrome (SRS) is a rare congenital disorder characterized by pre- and postnatal growth failure and dysmorphic features. Recently, pathogenic copy number variations (PCNVs) and imprinting defects other than hypomethylation of the H19-differentially methylated region (DMR) and maternal uniparental disomy chromosome 7 have been reported in patients with the SRS phenotype. This study aimed to clarify the frequency and clinical features of patients with SRS phenotype caused by PCNVs. We performed array comparative genomic hybridization analysis using a catalog array for 54 patients satisfying the Netchine-Harbison clinical scoring system (NH-CSS) (SRS-compatible) and for 28 patients presenting with three NH-CSS items together with triangular face and/or fifth finger clinodactyly and/or brachydactyly (SRS-like) without abnormal methylation levels of 9 DMRs related to known imprinting disorders. We then investigated the clinical features of patients with PCNVs. Three of the 54 SRS-compatible patients (5.6%) and 2 of the 28 SRS-like patients (7.1%) had PCNVs. We detected 3.5 Mb deletion in 4p16.3, mosaic trisomy 18, and 3.77–4.00 Mb deletion in 19q13.11-12 in SRS-compatible patients, and 1.41–1.97 Mb deletion in 7q11.23 in both SRS-like patients. Congenital heart diseases (CHDs) were identified in two patients and moderate to severe global developmental delay was observed in four patients. Of the patients in our study, 5.6% of SRS-compatible and 7.1% of SRS-like patients had PCNVs. All PCNVs have been previously reported for genetic causes of contiguous deletion syndromes or mosaic trisomy 18. Our study suggests patients with PCNVs, who have a phenotype resembling SRS, show a high tendency towards CHDs and/or apparent developmental delay.