表观遗传机制(MDEM)的孟德尔疾病是由基因突变引起的,其中相当一部分与表观遗传修饰有关。这些MDEM表现出广泛表征为多器官异常的表型重叠。在与表观遗传修饰相关的基因中检测到的变异可导致身材矮小并伴有多个系统异常。本研究旨在介绍和总结诊断率,临床,与MDEM相关的矮小身材的遗传特征。纳入了214名多器官异常的身材矮小患者。分析了这些患者的临床信息和全外显子组序列(WES)。WES在19个表观遗传调节基因中鉴定出33个致病性/可能的致病性变异(KMT2A,KMT2D,KDM6A,SETD5,KDM5C,HUWE1,UBE2A,NIPBL,SMC1A,RAD21,CREBBP,CUL4B,BPTF,ANKRD11,CHD7,SRCAP,CTCF,MECP2、UBE3A)共33例(15.4%)。值得注意的是,以前从未报道过19种变体。此外,这33种变异与16种不同的疾病相关,临床特征重叠,表现为发育迟缓/智力障碍(31/33;93.9%),小手(14/33;42.4%),第5指倾斜(14/33;42.4%),长睫毛(13/33;39.4%),听力障碍(9/33;27.3%)。此外,首次报道了几种相关的表型:与KMT2A变体的俱乐部,带有SETD5变体的网状颈部,视网膜脱离与CREBBP变体,稀疏侧眉与HUWE1变体,和长睑裂,下眼睑外侧三分之一外翻,SRCAP变异。结论:我们的研究为进一步理解身材矮小提供了一个新的概念框架。特定的临床发现可能表明身材矮小的患者可能具有表观遗传修饰的基因变体。
Mendelian disorders of the epigenetic machinery (MDEMs) are caused by genetic mutations, a considerable fraction of which are associated with epigenetic modification. These MDEMs exhibit phenotypic overlap broadly characterized by multiorgan abnormalities. The variant detected in genes associated with epigenetic modification can lead to short stature accompanied with multiple system abnormalities. This
study is aimed at presenting and summarizing the diagnostic rate, clinical, and genetic profile of MDEMs-associated short stature. Two hundred and fourteen short-stature patients with multiorgan abnormalities were enrolled. Clinical information and whole exome sequence (WES) were analyzed for these patients. WES identified 33 pathogenic/likely pathogenic variants in 19 epigenetic modulation genes (KMT2A, KMT2D, KDM6A, SETD5, KDM5C, HUWE1, UBE2A, NIPBL, SMC1A, RAD21, CREBBP, CUL4B, BPTF, ANKRD11, CHD7, SRCAP, CTCF, MECP2, UBE3A) in 33 patients (15.4%). Of note, 19 variants had never been reported previously. Furthermore, these 33 variants were associated with 16 different disorders with overlapping clinical features characterized by development delay/intelligence disability (31/33; 93.9%), small hands (14/33; 42.4%), clinodactyly of the 5th finger (14/33; 42.4%), long eyelashes (13/33; 39.4%), and hearing impairment (9/33; 27.3%). Additionally, several associated phenotypes are reported for the first time: clubbing with KMT2A variant, webbed neck with SETD5 variant, retinal detachment with CREBBP variant, sparse lateral eyebrow with HUWE1 variant, and long palpebral fissure with eversion of the lateral third of the low eyelid with SRCAP variant.Conclusions: Our
study provided a new conceptual framework for further understanding short stature. Specific clinical findings may indicate that a short-stature patient may have an epigenetic modified gene variant.