Histone Lysine Methylases and Demethylases
in the Landscape of Human Developmental Disorders
Autor corporativo
dc.contributor
Clinical Assessment of the
Utility of Sequencing and Evaluation as a Service (CAUSES) Study
Autor corporativo
dc.contributor
The Deciphering Developmental
Disorders (DDD) Study
Autor corporativo
dc.contributor
Siddharth Banka
Author
dc.contributor.author
Faundes, Víctor
Author
dc.contributor.author
Newman, William G.
Author
dc.contributor.author
Bernardini, Laura
Author
dc.contributor.author
Canham, Natalie
Author
dc.contributor.author
Clayton-Smith, Jill
Author
dc.contributor.author
Dallapiccola, Bruno
Author
dc.contributor.author
Davies, Sally J.
Author
dc.contributor.author
Demos, Michelle K.
Author
dc.contributor.author
Goldman, Amy
Author
dc.contributor.author
Gill, Harinder
Author
dc.contributor.author
Horton, Rachel
Author
dc.contributor.author
Kerr, Bronwyn
Author
dc.contributor.author
Kumar, Dhavendra
Author
dc.contributor.author
Lehman, Anna
Author
dc.contributor.author
McKee, Shane
Author
dc.contributor.author
Morton, Jenny
Author
dc.contributor.author
Parker, Michael J.
Author
dc.contributor.author
Rankin, Julia
Author
dc.contributor.author
Robertson, Lisa
Author
dc.contributor.author
Temple, Karen
Admission date
dc.date.accessioned
2019-03-18T12:01:14Z
Available date
dc.date.available
2019-03-18T12:01:14Z
Publication date
dc.date.issued
2018
Cita de ítem
dc.identifier.citation
The American Journal of Human Genetics 102, 175–187, January 4, 2018
Identifier
dc.identifier.issn
15376605
Identifier
dc.identifier.issn
00029297
Identifier
dc.identifier.other
10.1016/j.ajhg.2017.11.013
Identifier
dc.identifier.uri
https://repositorio.uchile.cl/handle/2250/167357
Abstract
dc.description.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 KMTand 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 spectrumof 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.