Inoue Takanobu, Nakamura Akie, Fuke Tomoko, Yamazawa Kazuki, Sano Shinichiro, Matsubara Keiko, Mizuno Seiji, Matsukura Yoshika, Harashima Chie, Hasegawa Tatsuji, Nakajima Hisakazu, Tsumura Kumi, Kizaki Zenro, Oka Akira, Ogata Tsutomu, Fukami Maki, Kagami Masayo
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, 2-10-1, Okura Setagaya-ku, Tokyo, 157-8535 Japan.
Department of Pediatrics, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655 Japan.
Clin Epigenetics. 2017 May 15;9:52. doi: 10.1186/s13148-017-0350-6. eCollection 2017.
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 -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.
Silver-Russell综合征（SRS）是一种罕见的先天性疾病，其特征为出生前和出生后的生长发育迟缓以及畸形特征。最近，已报道SRS表型患者存在致病性拷贝数变异（PCNVs）以及除差异甲基化区域（DMR）低甲基化和母源单亲二体7号染色体以外的印记缺陷。本研究旨在阐明由PCNVs引起的SRS表型患者的发生率及临床特征。
我们使用目录阵列对54例符合Netchine-Harbison临床评分系统（NH-CSS）（SRS兼容型）的患者以及28例呈现三项NH-CSS项目并伴有三角脸和/或第五指弯曲指和/或短指（SRS样）且与已知印记障碍相关的9个DMR甲基化水平无异常的患者进行了阵列比较基因组杂交分析。然后我们研究了PCNVs患者的临床特征。
54例SRS兼容型患者中有3例（5.6%）以及28例SRS样患者中有2例（7.1%）存在PCNVs。我们在SRS兼容型患者中检测到4p16.3区域3.5 Mb缺失、18号染色体嵌合三体以及19q13.11 - 12区域3.77 - 4.00 Mb缺失，在SRS样患者中均检测到7q11.23区域1.41 - 1.97 Mb缺失。两名患者被诊断患有先天性心脏病（CHDs），四名患者观察到中度至重度全面发育迟缓。
在我们的研究患者中，5.6%的SRS兼容型患者和7.1%的SRS样患者存在PCNVs。所有PCNVs先前均已报道为连续性缺失综合征或18号染色体嵌合三体的遗传原因。我们的研究表明，具有类似SRS表型的PCNVs患者患CHDs和/或明显发育迟缓的倾向较高。
