Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability

CAUSES Study, Deciphering Developmental Disorders Study

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)530-541
Number of pages12
JournalAmerican journal of human genetics
Volume104
Issue number3
DOIs
StatePublished - Mar 7 2019
Externally publishedYes

Fingerprint

Gene Components
Histone Acetyltransferases
Autistic Disorder
Intellectual Disability
Genetic Association Studies
Lip
Fibroblasts
Urogenital System
RNA Sequence Analysis
Multiprotein Complexes
Skin
Congenital Heart Defects
Ion Transport
DNA-Binding Proteins
Gene Expression Regulation
Eyelids
Acetylation
Nose
Histones
Lysine

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability. / CAUSES Study; Deciphering Developmental Disorders Study.

In: American journal of human genetics, Vol. 104, No. 3, 07.03.2019, p. 530-541.

Research output: Contribution to journalArticle

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abstract = "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.",
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T1 - Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability

AU - CAUSES Study

AU - Deciphering Developmental Disorders Study

AU - Cogné, Benjamin

AU - Ehresmann, Sophie

AU - Beauregard-Lacroix, Eliane

AU - Rousseau, Justine

AU - Besnard, Thomas

AU - Garcia, Thomas

AU - Petrovski, Slavé

AU - Avni, Shiri

AU - McWalter, Kirsty

AU - Blackburn, Patrick R.

AU - Sanders, Stephan J.

AU - Uguen, Kévin

AU - Harris, Jacqueline

AU - Cohen, Julie S.

AU - Blyth, Moira

AU - Lehman, Anna

AU - Berg, Jonathan

AU - Li, Mindy H.

AU - Kini, Usha

AU - Joss, Shelagh

AU - von der Lippe, Charlotte

AU - Gordon, Christopher T.

AU - Humberson, Jennifer B.

AU - Robak, Laurie

AU - Scott, Daryl A.

AU - Sutton, Vernon R.

AU - Skraban, Cara M.

AU - Johnston, Jennifer J.

AU - Poduri, Annapurna

AU - Nordenskjöld, Magnus

AU - Shashi, Vandana

AU - Gerkes, Erica H.

AU - Bongers, Ernie M.H.F.

AU - Gilissen, Christian

AU - Zarate, Yuri A.

AU - Kvarnung, Malin

AU - Lally, Kevin P.

AU - Kulch, Peggy A.

AU - Daniels, Brina

AU - Hernandez-Garcia, Andres

AU - Stong, Nicholas

AU - McGaughran, Julie

AU - Retterer, Kyle

AU - Tveten, Kristian

AU - Sullivan, Jennifer

AU - Geisheker, Madeleine R.

AU - Stray-Pedersen, Asbjorg

AU - Tarpinian, Jennifer M.

AU - Klee, Eric W.

AU - Stessman, Holly

PY - 2019/3/7

Y1 - 2019/3/7

N2 - 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.

AB - 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.

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DO - 10.1016/j.ajhg.2019.01.010

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JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

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