Baba Naomi, Lengyel Anna, Pinti Eva, Yapici Elzem, Schreyer Isolde, Liehr Thomas, Fekete György, Eggermann Thomas
Institute of Human Genetics, University of Jena, Jena, Germany.
Praxis Für Humangenetik, Zentrum Für Ambulante Medizin, Jena, Germany.
Mol Cytogenet. 2022 May 13;15(1):19. doi: 10.1186/s13039-022-00596-z.
Silver-Russell syndrome (SRS) is a genetic disorder characterized by intrauterine and postnatal growth restriction, relative macrocephaly at birth, body asymmetry and typical facial features. Clinical and molecular heterogeneity is described in SRS. Common causes are loss of methylation of the imprinting center 1 in 11p15 and maternal uniparental disomy of chromosome 7. Other genetic alterations include disturbances of imprinted regions in 14q32, 7q32 and 11p15 as well as submicroscopic deletions and duplications. Single nucleotide variants in genes like IGF2, HMGA2, PLAG1, CDKN1C have also been identified in patients with SRS phenotypes. However, routine molecular diagnostics usually focus on 11p15 and chromosome 7, while less frequent causes are not systematically addressed.
Here we report two patients with SRS features in which molecular karyotyping revealed microdeletions in 1q21 and 8q12.1 respectively. In a 3.5-year-old girl with postnatal growth restriction, feeding difficulties, relative macrocephaly and distinct SRS features a 2 Mb deletion in 1q21.1q21.2 was identified. Our second case is a 1.5-year-old boy with intrauterine and postnatal growth restriction, feeding difficulties and distinct facial features with a 77 kb deletion in 8q12.1 affecting PLAG1 as the only protein-encoding gene with known function.
The 1q21 region has not yet been assigned as an SRS region, although six patients with the same deletion and SRS features including relative macrocephaly have been described before. This new case adds to the evidence that distal 1q21 should be annotated as an SRS candidate region. The PLAGL1 alteration is the smallest deletion in 8q12.1 ever reported in a patient with SRS phenotype and it finally confirms that PLAG1 is the SRS causing gene in 8q12.1. To increase the diagnostic yield in patients with suspected SRS, we recommend both molecular karyotyping and next generation sequencing-based approaches.
Silver-Russell综合征（SRS）是一种遗传性疾病，其特征为宫内和出生后生长受限、出生时相对头大、身体不对称以及典型的面部特征。SRS存在临床和分子异质性。常见病因是11p15印记中心1的甲基化缺失以及7号染色体的母源单亲二体。其他遗传改变包括14q32、7q32和11p15印记区域的紊乱以及亚显微缺失和重复。在具有SRS表型的患者中也鉴定出了如IGF2、HMGA2、PLAG1、CDKN1C等基因的单核苷酸变异。然而，常规分子诊断通常聚焦于11p15和7号染色体，而较少见的病因未得到系统研究。
在此我们报告两名具有SRS特征的患者，分子核型分析分别在1q21和8q12.1发现了微缺失。在一名3.5岁有出生后生长受限、喂养困难、相对头大及明显SRS特征的女孩中，鉴定出1q21.1q21.2存在2 Mb缺失。我们的第二例是一名1.5岁男孩，有宫内和出生后生长受限、喂养困难及明显面部特征，8q12.1存在77 kb缺失，影响PLAG1，这是唯一已知功能的蛋白质编码基因。
尽管之前已描述过6名具有相同缺失及包括相对头大在内的SRS特征的患者，但1q21区域尚未被指定为SRS区域。这一新病例进一步证明1q21远端应被标注为SRS候选区域。PLAGL1改变是SRS表型患者中8q12.1报道过的最小缺失，最终证实PLAG1是8q12.1的SRS致病基因。为提高疑似SRS患者的诊断率，我们推荐分子核型分析和基于二代测序的方法。
