Abstract
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.
Highlights
The KMT2A gene, known as MLL, is on chr11q23 and encodes an H3K4 methyltransferase enzyme that regulates the expression of other genes including neuronal and homeobox-containing developmental genes.[1]
Using KMT2A variants from Whole-exome sequencing (WES) and wholegenome sequencing (WGS) studies (Supplementary Table 1 and Supplementary Data), we found that individuals ascertained for neurodevelopmental disorders (NDDs) were significantly enriched for de novo LoF and missense variants (p = 6.15 × 10−4) and de novo LoF variants alone (p = 1.92 × 10−3) when compared with controls, but not for de novo missense variants alone (p = 0.321) (Table 2)
To determine whether the de novo LoF and missense variants assort to certain regions of the KMT2A protein according to associated phenotypes, we examined the distribution of these variants
Summary
The KMT2A gene, known as MLL, is on chr11q23 and encodes an H3K4 methyltransferase enzyme that regulates the expression of other genes including neuronal and homeobox-containing developmental genes.[1]. Neurodevelopmental features and behavioural abnormalities were frequent, the lack of detailed neuropsychological assessments suggests the presence of these features may be underestimated and warrant further investigation.[7] Whole-exome sequencing (WES) and wholegenome sequencing (WGS) studies in individuals with neurodevelopmental disorders (NDDs), including Autism Spectrum Disorder (ASD), have revealed de novo KMT2A variants in 0.04 −2.17% of individuals with NDDs8–12 (refer to Supplementary Table 1 for additional references) These studies that identified KMT2A variants in WSS and NDD cohorts were performed independently, and a comprehensive analysis of NDD and WSS phenotypes together in individuals with KMT2A variants has not been conducted. We present the detailed clinical and genomic characterization of six unrelated individuals with de novo LoF or missense variants in KMT2A, and contextualize the findings with published literature
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
