Silver-Russell syndrome (SRS) is characterized by growth failure and dysmorphic features. Major (epi)genetic causes of SRS are loss of methylation on chromosome 11p15 (11p15 LOM) and maternal uniparental disomy of chromosome 7 (upd(7)mat). However, IGF2, CDKN1C, HMGA2, and PLAG1 mutations infrequently cause SRS. In addition, other imprinting disturbances, pathogenic copy number variations (PCNVs), and monogenic disorders sometimes lead to SRS phenotype. This study aimed to clarify the frequency and clinical features of the patients with gene mutations among etiology-unknown patients with SRS phenotype. Multigene sequencing was performed in 92 out of 336 patients referred to us for genetic testing for SRS. The clinical features of the patients were evaluated based on the Netchine-Harbison clinical scoring system. None of the patients showed 11p15 LOM, upd(7)mat, abnormal methylation levels for six differentially methylated regions (DMRs), namely, PLAGL1:alt-TSS-DMR on chromosome 6, KCNQ1OT1:TSS-DMR on chromosome 11, MEG3/DLK1:IG-DMR on chromosome 14, MEG3:TSS-DMR on chromosome 14, SNURF:TSS-DMR on chromosome 15, and GNAS A/B:TSS-DMR on chromosome 20, PCNVs, or maternal uniparental disomy of chromosome 16. Using next-generation sequencing and Sanger sequencing, we screened four SRS-causative genes and 406 genes related to growth failure and/or skeletal dysplasia. We identified four pathogenic or likely pathogenic variants in responsible genes for SRS (4.3%: IGF2 in two patients, CDKN1C, and PLAG1), and five pathogenic variants in causative genes for known genetic syndromes presenting with growth failure (5.4%: IGF1R abnormality (IGF1R), SHORT syndrome (PIK3R1), Floating-Harbor syndrome (SRCAP), Pitt-Hopkins syndrome (TCF4), and Noonan syndrome (PTPN11)). Functional analysis indicated the pathogenicity of the CDKN1C variant. The variants we detected in CDKN1C and PLAG1 were the second and third variants leading to SRS, respectively. Our patients with CDKN1C and PLAG1 variants showed similar phenotypes to previously reported patients. Furthermore, our data confirmed IGF1R abnormality, SHORT syndrome, and Floating-Harbor syndrome are differential diagnoses of SRS because of the shared phenotypes among these syndromes and SRS. On the other hand, the patients with pathogenic variants in causative genes for Pitt-Hopkins syndrome and Noonan syndrome were atypical of these syndromes and showed partial clinical features of SRS. We identified nine patients (9.8%) with pathogenic or likely pathogenic variants out of 92 etiology-unknown patients with SRS phenotype. This study expands the molecular spectrum of SRS phenotype.

中文翻译：

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基因突变对 Silver-Russell 综合征表型的贡献：对 92 名病因不明的患者进行多基因测序分析。


Silver-Russell 综合征 (SRS) 的特点是生长障碍和畸形特征。 SRS 的主要（表观）遗传原因是 11p15 号染色体 (11p15 LOM) 甲基化缺失和 7 号染色体母系单亲二体性 (upd(7)mat)。然而，IGF2、CDKN1C、HMGA2 和 PLAG1 突变很少引起 SRS。此外，其他印记干扰、致病性拷贝数变异 (PCNV) 和单基因疾病有时会导致 SRS 表型。本研究旨在明确病因不明的SRS表型患者中基因突变的频率和临床特征。在 336 名转诊至我们进行 SRS 基因检测的患者中，有 92 名患者进行了多基因测序。根据 Netchine-Harbison 临床评分系统评估患者的临床特征。没有患者表现出 11p15 LOM、upd(7)mat、六个差异甲基化区域 (DMR) 的异常甲基化水平，即 6 号染色体上的 PLAGL1:alt-TSS-DMR、11 号染色体上的 KCNQ1OT1:TSS-DMR、MEG3/ 14 号染色体上的 DLK1:IG-DMR、14 号染色体上的 MEG3:TSS-DMR、15 号染色体上的 SNURF:TSS-DMR、20 号染色体上的 GNAS A/B:TSS-DMR、PCNV 或 16 号染色体的母本单亲二体性。使用下一代测序和桑格测序，我们筛选了 4 个 SRS 致病基因和 406 个与生长障碍和/或骨骼发育不良相关的基因。我们在 SRS 的致病基因中发现了 4 个致病或可能的致病变异（4.3%：两名患者中的 IGF2，CDKN1C 和 PLAG1），以及已知生长障碍遗传综合征的致病基因中的 5 个致病变异（5.4%：IGF1R 异常） IGF1R)、短路综合征 (PIK3R1)、浮港综合征 (SRCAP)、皮特-霍普金斯综合征 (TCF4) 和努南综合征 (PTPN11)。 功能分析表明了 CDKN1C 变异的致病性。我们在 CDKN1C 和 PLAG1 中检测到的变异分别是导致 SRS 的第二个和第三个变异。我们的 CDKN1C 和 PLAG1 变异患者表现出与之前报道的患者相似的表型。此外，我们的数据证实 IGF1R 异常、短路综合征和浮港综合征是 SRS 的鉴别诊断，因为这些综合征和 SRS 具有共同的表型。另一方面，Pitt-Hopkins综合征和Noonan综合征致病基因携带致病性变异的患者则不典型，表现出部分SRS的临床特征。我们在 92 名病因不明的 SRS 表型患者中鉴定出 9 名患者 (9.8%) 具有致病性或可能致病性变异。这项研究扩展了 SRS 表型的分子谱。