Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability.
Adaptor Proteins, Signal Transducing
/ genetics
Adolescent
Adult
Amino Acid Sequence
Autistic Disorder
/ etiology
Child
Child, Preschool
Female
Genetic Association Studies
Humans
Infant
Intellectual Disability
/ etiology
Male
Mutation, Missense
Nuclear Proteins
/ genetics
Prognosis
Sequence Homology
Syndrome
Young Adult
TRRAP
autism spectrum disorder
congenital malformations
de novo variants
histone acetylation
intellectual disability
neurodevelopmental disorders
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
07 03 2019
07 03 2019
Historique:
received:
16
07
2018
accepted:
18
01
2019
pubmed:
5
3
2019
medline:
19
12
2019
entrez:
5
3
2019
Statut:
ppublish
Résumé
Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.
Identifiants
pubmed: 30827496
pii: S0002-9297(19)30010-2
doi: 10.1016/j.ajhg.2019.01.010
pmc: PMC6407527
pii:
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Nuclear Proteins
0
transformation-transcription domain-associated protein
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
530-541Subventions
Organisme : NICHD NIH HHS
ID : U54 HD083091
Pays : United States
Organisme : NINDS NIH HHS
ID : U01 NS077274
Pays : United States
Organisme : Intramural NIH HHS
ID : Z01 HG200328
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD064667
Pays : United States
Organisme : CIHR
Pays : Canada
Organisme : NHGRI NIH HHS
ID : UM1 HG006542
Pays : United States
Organisme : NINDS NIH HHS
ID : R35 NS105078
Pays : United States
Organisme : NHGRI NIH HHS
ID : K08 HG008986
Pays : United States
Organisme : NINDS NIH HHS
ID : U01 NS053998
Pays : United States
Organisme : NINDS NIH HHS
ID : U01 NS077364
Pays : United States
Organisme : NINDS NIH HHS
ID : U01 NS077303
Pays : United States
Organisme : NICHD NIH HHS
ID : U54 HD086984
Pays : United States
Organisme : NINDS NIH HHS
ID : U01 NS077276
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007266
Pays : United States
Organisme : Medical Research Council
ID : MR/M014568/1
Pays : United Kingdom
Organisme : NIMH NIH HHS
ID : R01 MH101221
Pays : United States
Informations de copyright
Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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