Haploinsufficiency of KMT2D is sufficient to cause Kabuki syndrome and is compatible with life

• Published in: Molecular Genetics & Genomic Medicine
• Main Authors: Luperchio, Teresa Romeo, Applegate, Carolyn D., Bodamer, Olaf, Björnsson, Hans Tómas
• Other Authors: Faculty of Medicine, Clinical Laboratory Services, Diagnostics and Blood Bank, Landspitali - The National University Hospital of Iceland
• Format: Other/Unknown Material
• Language: English
• Published: 2020
• Subjects: Kabuki heilkenni; Molecular Biology; Genetics; Genetics (clinical); Romeo; Iceland
• Online Access: https://hdl.handle.net/20.500.11815/3371; https://doi.org/10.1002/mgg3.1072

Funding Information: Teresa Romeo Luperchio Carolyn D. Applegate Olaf Bodamer Hans Tomas Bjornsson [e-mail] McKusick‐Nathans Department of Genetic Medicine Johns Hopkins University School of Medicine Baltimore MD USA Division of Genetics and Genomics Department of Pediatrics Boston Children's Hospital Harvard Medical School Boston MA USA Broad Institute of MIT and Harvard University Cambridge MA USA Department of Pediatrics Johns Hopkins University School of Medicine Baltimore MD USA Faculty of Medicine School of Health Sciences University of Iceland Reykjavik Iceland Landspitali University Hospital Reykjavik Iceland Icelandic Research Fund 195835‐051 Louma G Foundation Wellcome Trust We present the first patient described with haploinsufficency of KMT2D leading to Kabuki syndrome. Deletion of KMT2D has been thought to be lethal, but here we describe a patient with KMT2D deletion and classical Kabuki syndrome phenotype. Dear Editor, Kabuki syndrome (KS), also known as Niikawa‐Kuroki syndrome, is a Mendelian disorder of the epigenetic machinery which occurs in approximately 1:32,000 births characterized by intellectual disability, facial and limb dysmorphic features, and postnatal growth retardation. Pathogenic variants in genes KMT2D and KDM6A are found in 70% of patients with KS (type 1 MIM#:147920 and type 2 MIM#:300867 respectively). KMT2D and KDM6A are both highly constrained genes (pLI = 1.0) suggesting that both genes are intolerant to heterozygous loss‐of‐function variation and thus haploinsufficient. While true haploinsuffiency through deletion of the entire locus of ), no patient has yet to be described with a germline deletion of the entire KDM6A is a well‐established cause of KS2 (Lederer et al., KMT2D gene and it has been hypothesized that constitutional deletions of ). Despite this, KMT2D may be embryonic lethal in humans (Banka et al., KMT2D is classified in ClinGen as having sufficient evidence for haploinsufficiency based on the large number of truncating mutations that are causative of ...