Expanding the neurodevelopmental phenotypes of individuals with de novo KMT2A variants.
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Abstract: De novo loss-of-function (LoF) variants in theKMT2Agene are associated with Wiedemann−Steiner Syndrome (WSS). Recently, de novo KMT2 Avariants 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 KMT2 Avariants. From these data, we found that all six patients met clinical criteria for WSS and we further define the neurodevelopmental phenotypes associated with KMT2 Avariants 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 KMT2 Avariants, we also conducted a meta-analysis of individuals with KMT2 Avariants reported in the published literature. We found that de novo LoF or missense variants inKMT2Awere significantly more prevalent than predicted by a previously established statistical model of de novo mutation rate forKMT2A. Our genotype−phenotype findings better define the clinical spectrum associated withKMT2Avariants 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.