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