De novo loss-of-function (LoF) variants in the KMT2A gene are associated with Wiedemann−Steiner Syndrome (WSS). Recently, de novo KMT2A variants have been identified in sequencing studies of cohorts of individuals with neurodevelopmental disorders (NDDs). However, most of these studies lack the detailed clinical information required to determine whether those individuals have isolated NDDs or WSS (i.e. syndromic NDDs). We performed thorough clinical and neurodevelopmental phenotyping on six individuals with de novo KMT2A variants. From these data, we found that all six patients met clinical criteria for WSS and we further define the neurodevelopmental phenotypes associated with KMT2A variants and WSS. In particular, we identified a subtype of Autism Spectrum Disorder (ASD) in five individuals, characterized by marked rigid, repetitive and inflexible behaviours, emotional dysregulation, externalizing behaviours, but relative social motivation. To further explore the clinical spectrum associated with KMT2A variants, we also conducted a meta-analysis of individuals with KMT2A variants reported in the published literature. We found that de novo LoF or missense variants in KMT2A were significantly more prevalent than predicted by a previously established statistical model of de novo mutation rate for KMT2A. Our genotype−phenotype findings better define the clinical spectrum associated with KMT2A variants and suggest that individuals with de novo LoF and missense variants likely have a clinically unrecognized diagnosis of WSS, rather than isolated NDD or ASD alone. This highlights the importance of a clinical genetic and neurodevelopmental assessment for individuals with such variants in KMT2A.

KMT2A基因中的从头功能丧失 (LoF) 变异与维德曼-斯坦纳综合征 (WSS) 相关。最近，在神经发育障碍 (NDD) 个体队列研究中发现了新的KMT2A变异。然而，大多数这些研究缺乏确定这些个体是否患有孤立性NDD或WSS（即综合征性NDD）所需的详细临床信息。我们对 6 名具有 de novo KMT2A变异的个体进行了彻底的临床和神经发育表型分析。从这些数据中，我们发现所有六名患者均符合 WSS 的临床标准，并且我们进一步定义了与KMT2A变异和 WSS 相关的神经发育表型。特别是，我们在五个人身上发现了自闭症谱系障碍 (ASD) 的亚型，其特征是明显的僵化、重复和不灵活的行为、情绪失调、外化行为，但具有相对的社会动机。为了进一步探索与KMT2A变异相关的临床谱，我们还对已发表文献中报道的具有KMT2A变异的个体进行了荟萃分析。我们发现KMT2A中的从头 LoF 或错义变异比先前建立的KMT2A从头突变率统计模型预测的更为普遍。我们的基因型-表型研究结果更好地定义了与KMT2A变异相关的临床谱，并表明具有新发 LoF 和错义变异的个体可能具有临床上未被识别的 WSS 诊断，而不是单独的孤立的 NDD 或 ASD。 这凸显了对KMT2A具有此类变异的个体进行临床遗传和神经发育评估的重要性。