Trithorax相关H3K4甲基转移酶,KMT2C和KMT2D,是关键的表观遗传修饰剂。KMT2C的单倍功能不全最近才被认为是神经发育障碍(NDD)的原因,因此KMT2C相关NDD(现称为Kleefstra综合征2)的临床和分子谱在很大程度上是未知的.我们确定了98例具有罕见KMT2C变体的个体,包括75个蛋白质截短变体(PTV)。值得注意的是,15%的KMT2CPTV是遗传的。尽管最高表达的KMT2C转录物仅由最后四个外显子组成,在这个大基因的几乎所有外显子中都发现了致病性PTV。由于分段重复和克隆性造血引起的伪影,KMT2C变体解释可能具有挑战性。使用来自27个受影响个体的样本,分为发现和验证队列,我们产生了中度强度障碍特异性KMT2CDNA甲基化(DNAm)特征,并证明了其在分类非截短变体中的实用性.基于81名具有致病性/可能的致病性变异的个体,我们证明与KMT2C相关的NDD具有发育迟缓的特征,智力残疾,行为和精神问题,低张力,癫痫发作,身材矮小,和其他合并症。PhenoScore的面部模块,适用于34名受影响个人的照片,揭示了KMT2C相关的面部完形与一般NDD人群有显著差异。最后,使用PhenoScore和DNAM签名,我们证明KMT2C相关NDD在临床和表观遗传上与Kleefstra和Kabuki综合征不同.总的来说,我们定义了临床特征,分子光谱,与KMT2C相关的NDD的DNAm签名,并证明它们与Kleefstra和Kabuki综合征不同,强调需要重命名这种情况。
Trithorax-related H3K4 methyltransferases, KMT2C and KMT2D, are critical epigenetic modifiers. Haploinsufficiency of KMT2C was only recently recognized as a cause of neurodevelopmental disorder (NDD), so the clinical and molecular spectrums of the KMT2C-related NDD (now designated as Kleefstra syndrome 2) are largely unknown. We ascertained 98 individuals with rare KMT2C variants, including 75 with protein-truncating variants (PTVs). Notably, ∼15% of KMT2C PTVs were inherited. Although the most highly expressed KMT2C transcript consists of only the last four exons, pathogenic PTVs were found in almost all the exons of this large gene. KMT2C variant interpretation can be challenging due to segmental duplications and clonal hematopoesis-induced artifacts. Using samples from 27 affected individuals, divided into discovery and validation cohorts, we generated a moderate strength disorder-specific KMT2C DNA methylation (DNAm) signature and demonstrate its utility in classifying non-truncating variants. Based on 81 individuals with pathogenic/likely pathogenic variants, we demonstrate that the KMT2C-related NDD is characterized by developmental delay, intellectual disability, behavioral and psychiatric problems, hypotonia, seizures, short stature, and other comorbidities. The facial module of PhenoScore, applied to photographs of 34 affected individuals, reveals that the KMT2C-related facial gestalt is significantly different from the general NDD population. Finally, using PhenoScore and DNAm signatures, we demonstrate that the KMT2C-related NDD is clinically and epigenetically distinct from Kleefstra and Kabuki syndromes. Overall, we define the clinical features, molecular spectrum, and DNAm signature of the KMT2C-related NDD and demonstrate they are distinct from Kleefstra and Kabuki syndromes highlighting the need to rename this condition.