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Histone lysine methylases and demethylases in the landscape of human developmental disorders

Histone lysine methylases and demethylases in the landscape of human developmental disorders
Histone lysine methylases and demethylases in the landscape of human developmental disorders

Histone lysine methyltransferases (KMTs) and demethylases (KDMs) underpin gene regulation. Here we demonstrate that variants causing haploinsufficiency of KMTs and KDMs are frequently encountered in individuals with developmental disorders. Using a combination of human variation databases and existing animal models, we determine 22 KMTs and KDMs as additional candidates for dominantly inherited developmental disorders. We show that KMTs and KDMs that are associated with, or are candidates for, dominant developmental disorders tend to have a higher level of transcription, longer canonical transcripts, more interactors, and a higher number and more types of post-translational modifications than other KMT and KDMs. We provide evidence to firmly associate KMT2C, ASH1L, and KMT5B haploinsufficiency with dominant developmental disorders. Whereas KMT2C or ASH1L haploinsufficiency results in a predominantly neurodevelopmental phenotype with occasional physical anomalies, KMT5B mutations cause an overgrowth syndrome with intellectual disability. We further expand the phenotypic spectrum of KMT2B-related disorders and show that some individuals can have severe developmental delay without dystonia at least until mid-childhood. Additionally, we describe a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly. Collectively, these results emphasize the significance of histone lysine methylation in normal human development and the importance of this process in human developmental disorders. Our results demonstrate that systematic clinically oriented pathway-based analysis of genomic data can accelerate the discovery of rare genetic disorders.

Journal Article
0002-9297
175-187
Faundes, Víctor
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Newman, William G
86437772-985f-4e4f-94fe-c7fdd70a87b6
Bernardini, Laura
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Canham, Natalie
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Clayton-Smith, Jill
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Dallapiccola, Bruno
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Davies, Sally J
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Demos, Michelle K
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Goldman, Amy
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Gill, Harinder
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Horton, Rachel
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Kerr, Bronwyn
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Kumar, Dhavendra
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Lehman, Anna
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McKee, Shane
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Morton, Jenny
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Parker, Michael J
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Rankin, Julia
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Robertson, Lisa
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Temple, I Karen
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Banka, Siddharth
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Clinical Assessment of the Utility of Sequencing and Evaluation as a Service (CAUSES) Study
Faundes, Víctor
9080ea95-206d-48d1-92ac-47b199f73622
Newman, William G
86437772-985f-4e4f-94fe-c7fdd70a87b6
Bernardini, Laura
9c347671-3b5d-4ccf-bfef-cdc7a2f44dbe
Canham, Natalie
4ea07141-98e1-4f20-8d96-5473a8499389
Clayton-Smith, Jill
df8946ac-9da9-4ef2-b180-f468a5424844
Dallapiccola, Bruno
dcdfadf2-21dc-49d6-8b54-d5f6e994d200
Davies, Sally J
119090f2-fa05-4005-aea2-41c68e06adbd
Demos, Michelle K
aeba2c65-c11a-4641-b9bd-e44d4a5e61cf
Goldman, Amy
d3a8ad5c-2cb0-4137-9d8a-7eade9c7d4b3
Gill, Harinder
e746c8e0-7952-4b36-a91c-fe0ab22b8644
Horton, Rachel
696bc772-e426-4b24-920e-a071a097d05d
Kerr, Bronwyn
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Kumar, Dhavendra
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Lehman, Anna
dbba1555-0ff7-4e87-9b00-604123bb7baf
McKee, Shane
697d9bc8-c8dd-43dd-b829-1f4bcf0c2c82
Morton, Jenny
974fa57c-da06-4c76-b5b3-19629ec20d59
Parker, Michael J
9a223cab-0ee5-417e-93e4-199f139f3ffc
Rankin, Julia
e10a0f80-2929-4b47-8fa2-8dee01ce39c6
Robertson, Lisa
f038359c-ff35-40eb-a859-1281c1649687
Temple, I Karen
d63e7c66-9fb0-46c8-855d-ee2607e6c226
Banka, Siddharth
26126fbc-e373-4dfa-959f-faa79129828b

Faundes, Víctor, Newman, William G, Bernardini, Laura, Canham, Natalie, Clayton-Smith, Jill, Dallapiccola, Bruno, Davies, Sally J, Demos, Michelle K, Goldman, Amy, Gill, Harinder, Horton, Rachel, Kerr, Bronwyn, Kumar, Dhavendra, Lehman, Anna, McKee, Shane, Morton, Jenny, Parker, Michael J, Rankin, Julia, Robertson, Lisa, Temple, I Karen and Banka, Siddharth , Clinical Assessment of the Utility of Sequencing and Evaluation as a Service (CAUSES) Study (2018) Histone lysine methylases and demethylases in the landscape of human developmental disorders. The American Journal of Human Genetics, 102 (1), 175-187. (doi:10.1016/j.ajhg.2017.11.013).

Record type: Article

Abstract

Histone lysine methyltransferases (KMTs) and demethylases (KDMs) underpin gene regulation. Here we demonstrate that variants causing haploinsufficiency of KMTs and KDMs are frequently encountered in individuals with developmental disorders. Using a combination of human variation databases and existing animal models, we determine 22 KMTs and KDMs as additional candidates for dominantly inherited developmental disorders. We show that KMTs and KDMs that are associated with, or are candidates for, dominant developmental disorders tend to have a higher level of transcription, longer canonical transcripts, more interactors, and a higher number and more types of post-translational modifications than other KMT and KDMs. We provide evidence to firmly associate KMT2C, ASH1L, and KMT5B haploinsufficiency with dominant developmental disorders. Whereas KMT2C or ASH1L haploinsufficiency results in a predominantly neurodevelopmental phenotype with occasional physical anomalies, KMT5B mutations cause an overgrowth syndrome with intellectual disability. We further expand the phenotypic spectrum of KMT2B-related disorders and show that some individuals can have severe developmental delay without dystonia at least until mid-childhood. Additionally, we describe a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly. Collectively, these results emphasize the significance of histone lysine methylation in normal human development and the importance of this process in human developmental disorders. Our results demonstrate that systematic clinically oriented pathway-based analysis of genomic data can accelerate the discovery of rare genetic disorders.

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Accepted/In Press date: 17 November 2017
e-pub ahead of print date: 21 December 2017
Published date: 4 January 2018
Additional Information: Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Keywords: Journal Article

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Local EPrints ID: 417113
URI: https://eprints.soton.ac.uk/id/eprint/417113
ISSN: 0002-9297
PURE UUID: 420180fb-b12e-4287-a0ed-67b574897839

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Date deposited: 19 Jan 2018 17:30
Last modified: 06 Jul 2018 04:01

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Contributors

Author: Víctor Faundes
Author: William G Newman
Author: Laura Bernardini
Author: Natalie Canham
Author: Jill Clayton-Smith
Author: Bruno Dallapiccola
Author: Sally J Davies
Author: Michelle K Demos
Author: Amy Goldman
Author: Harinder Gill
Author: Rachel Horton
Author: Bronwyn Kerr
Author: Dhavendra Kumar
Author: Anna Lehman
Author: Shane McKee
Author: Jenny Morton
Author: Michael J Parker
Author: Julia Rankin
Author: Lisa Robertson
Author: I Karen Temple
Author: Siddharth Banka

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