Li Qiuyue, Sun Chengjun, Yang Lin, Lu Wei, Luo Feihong
Department of Pediatric Endocrinology and Inherited Metabolic Diseases, Children's Hospital of Fudan University, Shanghai, China.
Transl Pediatr. 2021 Apr;10(4):834-842. doi: 10.21037/tp-20-385.
Patients with KBG Syndrome due to mutations and 16q24.3 microdeletions including were identified. Classical and most frequent phenotypes include various degrees of intelligence disability (ID), short stature (SS), delayed bone age, macrodontia, distinctive facial features and skeletal anomalies. The variable expressivity of KBG syndrome makes it challenging to establish genotype-phenotype correlations, which also affects further studies for this novel syndrome. We aim to report three unrelated patients with KBG syndrome caused by gene pathological variants and to evaluate potential associations among gene variant types, the 16q24.3 microdeletion, and the clinical spectrum of KBG syndrome.
The genetic etiology of three unreported KBG patients was identified by whole exome sequencing and confirmed via Sanger sequencing. Literature review was conducted to summarize the phenotype-genotype relationship based on three unreported Chinese cases and 186 reported cases.
Two pathological variants (c.7407dupC, p.P2530Rfs61; c.G3046A, p.D1016N) and one reported variant (c.6792dupC, p. P2271Pfs8) were detected in our patients. Compared with the 16q24.3 microdeletion, patients harboring gene mutations showed significantly higher frequency of malformations including macrodontia, long philtrum, abnormal eyebrows, widely spaced eyes, anteverted nares, eyelid ptosis, brachydactyly, brachycephaly (P<0.05), and significantly lower risk of congenital heart diseases and frontal bossing (P<0.05). The intellectual disability (ID) was significantly milder among patients carrying truncating variants located between repression domain 1 (RD1) and activation domain (AD) than those carrying mutations disrupting repression domain 2 (RD2) alone and disrupting all functional domain (RD1, AD or RD2) (P<0.05).
Novel pathological variants harbored in the gene contribute to the KBG syndrome variant spectrum. gene variants disrupting RD1 and RD2 or RD2 alone are more likely to have more severe ID, which warrants different intervention strategies for KBG syndrome.
已鉴定出因基因突变和16q24.3微缺失（包括 ）导致的KBG综合征患者。典型且最常见的表型包括不同程度的智力残疾（ID）、身材矮小（SS）、骨龄延迟、巨牙症、独特的面部特征和骨骼异常。KBG综合征的可变表达性使得建立基因型 - 表型相关性具有挑战性，这也影响了对这种新综合征的进一步研究。我们旨在报告3例由 基因病理变异引起的无关的KBG综合征患者，并评估 基因变异类型、16q24.3微缺失与KBG综合征临床谱之间的潜在关联。
通过全外显子组测序确定3例未报道的KBG患者的遗传病因，并通过桑格测序进行确认。进行文献综述以基于3例未报道的中国病例和186例报道病例总结表型 - 基因型关系。
在我们的患者中检测到2种病理变异（c.7407dupC，p.P2530Rfs61；c.G3046A，p.D1016N）和1种已报道的变异（c.6792dupC，p.P2271Pfs8）。与16q24.3微缺失相比，携带 基因突变的患者出现包括巨牙症、长人中、异常眉毛、眼距增宽、鼻孔前倾、眼睑下垂、短指畸形、短头畸形等畸形的频率显著更高（P<0.05），而先天性心脏病和额部突出的风险显著更低（P<0.05）。与单独携带破坏抑制结构域2（RD2）的突变以及破坏所有功能结构域（RD1、AD或RD2）的患者相比，携带位于抑制结构域1（RD1）和激活结构域（AD）之间的截短变异的患者智力残疾（ID）明显较轻（P<0.05）。
基因中存在的新病理变异有助于丰富KBG综合征的变异谱。破坏RD1和RD2或仅破坏RD2的 基因变异更有可能导致更严重的ID，这为KBG综合征的不同干预策略提供了依据。
