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Genet Med. 2020 Jan 17. doi: 10.1038/s41436-019-0743-3. [Epub ahead of print]

A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome.

Author information

1
Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, Manchester, UK.
2
Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, Manchester, UK.
3
Leeds Institute of Medical Research, Faculty of Medicine and Health, The University of Leeds, Leeds, UK.
4
Department of Clinical Genetics, Chapel Allerton Hospital, Leeds Teaching Hospitals Trust, Leeds, UK.
5
Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, The University of Leeds, Leeds, UK.
6
Division of Developmental Biology & Medicine, School of Biological Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, Manchester, UK.
7
Centre of Genetics & Genomics Versus Arthritis, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester, UK.
8
Department of Paediatrics, College of Medicine & Health Sciences, United Arab University, Al-Ain, UAE.
9
Liverpool Centre for Genomic Medicine, Liverpool Women's NHS Foundation Trust, Liverpool, UK.
10
North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, UK.
11
Laboratorio de Genética y Enfermedades Metabólicas, Instituto de Nutrición y Tecnología de los Alimentos, Universidad de Chile, Santiago, Chile.
12
Department of Clinical Genetics, Guy's & St Thomas NHS Foundation Trust, London, UK.
13
Department of Paediatrics, Tawam Hospital, Al-Ain, UAE.
14
Temple street Children's University Hospital, Dublin, Ireland.
15
Wellcome Trust Sanger Institute, Cambridge, UK.
16
Medical Genetics Unit, St. Orsola-Malpighi, University of Bologna, Bologna, Italy.
17
Molecular and Clinical Sciences Research Institute, St George's University of London, London, UK.
18
Department of Medical & Molecular Genetics, King's College London, London, UK.
19
Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.
20
Queen Mary University of London, London, UK.
21
Clinical Psychology Department, Royal Manchester Children's Hospital, Manchester University Foundation NHS Trust, Health Innovation Manchester, Manchester, UK.
22
Molecular Genetics Department, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
23
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
24
Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, Manchester, UK. Siddharth.Banka@manchester.ac.uk.
25
Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester University Foundation NHS Trust, Health Innovation Manchester, Manchester, UK. Siddharth.Banka@manchester.ac.uk.

Abstract

PURPOSE:

To investigate if specific exon 38 or 39 KMT2D missense variants (MVs) cause a condition distinct from Kabuki syndrome type 1 (KS1).

METHODS:

Multiple individuals, with MVs in exons 38 or 39 of KMT2D that encode a highly conserved region of 54 amino acids flanked by Val3527 and Lys3583, were identified and phenotyped. Functional tests were performed to study their pathogenicity and understand the disease mechanism.

RESULTS:

The consistent clinical features of the affected individuals, from seven unrelated families, included choanal atresia, athelia or hypoplastic nipples, branchial sinus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations, and thyroid abnormalities. None of the individuals had intellectual disability. The frequency of clinical features, objective software-based facial analysis metrics, and genome-wide peripheral blood DNA methylation patterns in these patients were significantly different from that of KS1. Circular dichroism spectroscopy indicated that these MVs perturb KMT2D secondary structure through an increased disordered to ɑ-helical transition.

CONCLUSION:

KMT2D MVs located in a specific region spanning exons 38 and 39 and affecting highly conserved residues cause a novel multiple malformations syndrome distinct from KS1. Unlike KMT2D haploinsufficiency in KS1, these MVs likely result in disease through a dominant negative mechanism.

KEYWORDS:

KMT2D; Kabuki syndrome; histone 3 lysine 4 methyltransferase; intrinsically disordered region; multiple congenital anomaly

PMID:
31949313
DOI:
10.1038/s41436-019-0743-3

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