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. 2019 Apr 26:4:9.
doi: 10.1038/s41525-019-0083-x. eCollection 2019.

Expanding the neurodevelopmental phenotypes of individuals with de novo KMT2A variants

Ada J S Chan  1   2 , Cheryl Cytrynbaum  2   3   4   5 , Ny Hoang  2   3   4   5   6 , Patricia M Ambrozewicz  6   7 , Rosanna Weksberg  2   3   4   8   9 , Irene Drmic  10 , Anne Ritzema  6   7 , Russell Schachar  11   12 , Susan Walker  1 , Mohammed Uddin  1   13 , Mehdi Zarrei  1 , Ryan K C Yuen  1   2   4 , Stephen W Scherer  1   2   4   8   14
Affiliations

Expanding the neurodevelopmental phenotypes of individuals with de novo KMT2A variants

Ada J S Chan et al. NPJ Genom Med. .

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.

Keywords: Autism spectrum disorders; Disease genetics.

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Conflict of interest statement

S.W.S. is on the Scientific Advisory committees of Population Bio and Deep Genomics. Athena Diagnostics and Lineagen license intellectual property from the Hospital for Sick Children based on research from his laboratory. These relationships did not influence data interpretation or presentation during this study, but are still being disclosed for potential future considerations. The other authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Facial features of six novel patients with de novo LoF or missense variants in KMT2A. a Patient 1 at 10 years; b patient 2 at 9 years; c patient 3 at 13 years; d Patient 4 at 25 years; e patient 5 at 5 years; f patient 6 at 1 year of age. Characteristic facial features noted in these patients include: thick and/or high arched eyebrows, long eyelashes, hypertelorism, downslanting palpebral fissures and a broad nasal tip. Written consent was obtained from all patients for open access publication of the photographs. LoF: loss-of-function
Fig. 2
Fig. 2
Hypertrichosis of the arms and legs of patient 2 at 9 years of age. Written consent was obtained from patient 2 for open access publication of the photographs
Fig. 3
Fig. 3
Distribution of de novo LoF, missense, and deletion variants in KMT2A from novel cases and individuals from meta-analysis. One hundred and three de novo LoF, 24 de novo missense, and two de novo deletion variants are plotted on the KMT2A protein (NM_001197104.1) with the protein coordinates below. The six new patients are shown with Human Genome Variation Society nomenclature. The two black arrows indicate the two taspase 1 cleavage sites that generate the N-terminal and C-terminal fragment. Size of the circle or square is proportional to the number of individuals with that specific KMT2A variant. LoF: loss-of-function
Fig. 4
Fig. 4
Spectrum of reported neurodevelopmental and neurological phenotypes of 127 individuals with de novo LoF or missense variants in KMT2A. Frequencies of neurodevelopmental and neurological phenotypes reported in publications are shown. Note that absence of phenotype from a publication either means the phenotype was not assessed or there was a negative finding, which we could not distinguish in most publications. LoF: loss-of-function
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