Broad neurodevelopmental features and cortical anomalies associated with a novel de novo KMT2A variant in Wiedemann−Steiner syndrome

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Abstract

Wiedemann-Steiner syndrome (WDSTS) is a rare genetic disorder including developmental delay/intellectual disability (DD/ID), hypertrichosis cubiti, short stature, and distinctive facial features, caused by mutation in KMT2A gene, which encodes a histone methyltransferase (H3K4) that regulates chromatin-mediated transcription. Different neurodevelopmental phenotypes have been described within the WDSTS spectrum, including a peculiar Autism Spectrum Disorder (ASDs) subtype in some affected individuals.

Here, we report a 9-year-old Caucasian male found by next-generation panel sequencing to carry a novel heterozygous de novo KMT2A frameshift variant (NM_001197104.2:c.4433delG; p. Arg1478LeufsTer108). This boy presented a WDSTS phenotype associated with broad neurodevelopmental features, including an unusual speech difficulty (i.e., palilalia), and brain imaging studies revealed an array of cortical anomalies (e.g., frontal simplified gyration, focal frontal cortical dysplasia). These clinical and radiological observations expand the known WDSTS-related neurodevelopmental phenotypes and further strengthen the important role of KMT2A in brain function and cortical development.

Introduction

Wiedemann-Steiner syndrome (WDSTS, MIM 605130) is a rare clinical condition which includes developmental delay/intellectual disability (DD/ID), hypertrichosis cubiti, short stature, and distinctive facial features and is caused by heterozygous variants in KMT2A (MIM: 159,555; also known as MLL1). This gene encodes a histone methyltransferase (H3K4) that regulates chromatin-mediated transcription, including the expression of multiple Hox and Wnt genes (Jones et al., 2012). During the last decade, the increasing use of next-generation sequencing (NGS) technologies including whole exome sequencing (WES), led to identification of (at least) 70 individuals carrying KMT2A mutations (Chan et al., 2019). This highlighted a broad phenotypic spectrum associated with WDSTS, with several patients also presenting heterogeneous neurodevelopmental phenotypes including Autism Spectrum Disorder (ASD) subtypes characterized by marked rigid, repetitive and inflexible behaviours, emotional dysregulation, externalizing behaviours, but relatively conserved social motivation (Chan et al., 2019).

In this study, we describe a 9-year-old Caucasian male carrying a novel de novo KMT2A frameshift variant, (NM_001197104.2: c.4433delG; p.Arg1478LeufsTer108), associated with WDSTS phenotype and additional neurodevelopmental and neuroradiological anomalies.

Section snippets

Clinical report

This study was approved by the ethics committee Palermo 1 of “Paolo Giaccone” University Hospital of Palermo, Italy. Written informed consent for publication was obtained from patient's parents. The proband is the only male child of apparently healthy unrelated parents whose cognitive, social and academic functioning was adequate. He was born at 38th week of gestation by caesarean section, following an uneventful pregnancy. APGAR scores were 7–9; his birth weight was 2690 g (z −1.04), height

Discussion

Since the first descriptions of WDSTS, hypertrichosis has been regarded as a peculiar clinical feature associated with this syndrome (Jones et al., 2012; Steiner and Marques, 2000; Sun et al., 2017). However, both before and after the identification of KMT2A as causative gene for this condition, several reports have shown that hypertrichosis (in both cubiti and lower spine) has only been found in a proportion of patients (approximately 60–75%) and also should not be considered as pathognomonic

Disclosure

All authors read and approved the final version of this manuscript.

Funding

No funding secured for this study.

Authors statement

All authors have seen the observations of the reviewers and they agree with the changes made.

Informed consent

Written informed consent for publication was obtained from patient's parents.

Ethics approval and consent to participate

The study was approved by the ethics committee Palermo 1 of University Hospital.

Declaration of competing interest

The authors declare that they have no conflict of interest.

Acknowledgements

We thank the child and his parents who participated in this study. We thank Prof. Renzo Guerrini and Dr. Elena Parrini for expert advice in performing and interpretation of genetic analysis. We acknowledge Dr. Vincenzo Antona for his advice and support in genetic counselling.

References (15)

  • T. Benke et al.

    Palilalia and repetitive speech: two case studies

    Brain Lang.

    (2001)
  • W.D. Jones et al.

    De novo mutations in MLL cause Wiedemann-Steiner syndrome

    Am. J. Hum. Genet.

    (2012)
  • S. Baer et al.

    Wiedemann-Steiner syndrome as a major cause of syndromic intellectual disability: a study of 33 French cases

    Clin. Genet.

    (2018)
  • A.J.S. Chan et al.

    Expanding the neurodevelopmental phenotypes of individuals with de novo KMT2A variants

    NPJ Genom Med

    (2019)
  • Y.C. Huang et al.

    The epigenetic factor Kmt2a/Mll1 regulates neural progenitor proliferation and neuronal and glial differentiation

    Dev Neurobiol

    (2015)
  • M. Jakovcevski et al.

    Neuronal Kmt2a/Mll1 histone methyltransferase is essential for prefrontal synaptic plasticity and working memory

    J. Neurosci.

    (2015)
  • N. Li et al.

    Description of the molecular and phenotypic spectrum of Wiedemann-Steiner syndrome in Chinese patients

    Orphanet J. Rare Dis.

    (2018)
There are more references available in the full text version of this article.
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