PDF(Pubmed)
Abstract：
SOX11 is a transcription factor belonging to the sex determining region Y-related high-mobility group box family that plays a vital role in early embryogenesis and neurogenesis. De novo variants in SOX11 have been initially reported to cause a rare neurodevelopmental disorder, mainly referred to Coffin-siris syndrome 9 (CSS9, OMIM# 615866) which is characterized with growth deficiency, intellectual disability (ID), microcephaly, coarse facies, and hypoplastic nails of the fifth fingers and/or toes. A recent large-scale cohort study suggests that SOX11 variation would result in a clinically and molecularly distinct disease from CSS. Here, we describe three unrelated Chinese cases with variable phenotype, mainly involving developmental delay, ID, short statute, microcephaly, facial deformities (i.e., prominent forehead, arched eye brow, flat nasal bridge, broad nose and short philtrum), and cryptorchidism. Whole-exome sequencing (WES) revealed three novel heterozygous variants in the SOX11 gene, including two missense variants of c.337T>C (p.Y113H) and c.425C>G (p.A142G), and one nonsense variant of c.820A>T (p. K142*). Luciferase reporting assay shows that the two missense variants impair the transcriptional activity of the SOX11 target gene GDF5. Additionally, WES uncovered a 4,300 kb deletion involving the region of 1q24.2-q25.1 (hg19,chr1:169,433,149-173,827,682) in patient 1, which also contributes to the condition of the patient. In summary, this is the first report of Chinese cases with de novo variants of SOX11. Our study partially supports the previous observation that the phenotype caused by SOX11 variants somewhat differs from classical CSS.
摘要：
SOX11是一种转录因子，属于性别决定区Y相关的高迁移率族盒家族，在早期胚胎发生和神经发生中起着至关重要的作用。最初报道SOX11中的从头变异会导致一种罕见的神经发育障碍，主要指Coffin-siris综合征9（CSS9，OMIM#615866），其特征是生长不足，智力残疾（ID），小头畸形,粗糙相,和第五手指和/或脚趾的发育不良指甲。最近的大规模队列研究表明，SOX11变异将导致与CSS在临床和分子上不同的疾病。这里,我们描述了三个不相关的中国病例，具有可变的表型，主要涉及发育迟缓，ID,简短的法规，小头畸形,面部畸形(即，突出的前额,拱形的眉毛，扁平鼻梁,宽阔的鼻子和短的人)，和隐睾。全外显子组测序（WES）揭示了SOX11基因中的三个新的杂合变体，包括c.337T>C的两个错义变体（p。Y113H）和c.425C>G（p。A142G),和c.820A>T的一个无义变体（p。K142*).荧光素酶报告测定显示,两个错义变体损害SOX11靶基因GDF5的转录活性。此外,WES在患者1中发现了涉及1q24.2-q25.1（hg19，chr1：169,433,149-173,827,682）区域的4,300kb缺失，这也有助于患者的病情。总之,这是首次报道SOX11的中国病例。我们的研究部分支持以前的观察，即SOX11变体引起的表型与经典CSS有些不同。
