Dataset Information

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

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.

SUBMITTER: Cogne B

PROVIDER: S-EPMC6407527 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Cogné Benjamin B Ehresmann Sophie S Beauregard-Lacroix Eliane E Rousseau Justine J Besnard Thomas T Garcia Thomas T Petrovski Slavé S Avni Shiri S McWalter Kirsty K Blackburn Patrick R PR Sanders Stephan J SJ Uguen Kévin K Harris Jacqueline J Cohen Julie S JS Blyth Moira M Lehman Anna A Berg Jonathan J Li Mindy H MH Kini Usha U Joss Shelagh S von der Lippe Charlotte C Gordon Christopher T CT Humberson Jennifer B JB Robak Laurie L Scott Daryl A DA Sutton Vernon R VR Skraban Cara M CM Johnston Jennifer J JJ Poduri Annapurna A Nordenskjöld Magnus M Shashi Vandana V Gerkes Erica H EH Bongers Ernie M H F EMHF Gilissen Christian C Zarate Yuri A YA Kvarnung Malin M Lally Kevin P KP Kulch Peggy A PA Daniels Brina B Hernandez-Garcia Andres A Stong Nicholas N McGaughran Julie J Retterer Kyle K Tveten Kristian K Sullivan Jennifer J Geisheker Madeleine R MR Stray-Pedersen Asbjorg A Tarpinian Jennifer M JM Klee Eric W EW Sapp Julie C JC Zyskind Jacob J Holla Øystein L ØL Bedoukian Emma E Filippini Francesca F Guimier Anne A Picard Arnaud A Busk Øyvind L ØL Punetha Jaya J Pfundt Rolph R Lindstrand Anna A Nordgren Ann A Kalb Fayth F Desai Megha M Ebanks Ashley Harmon AH Jhangiani Shalini N SN Dewan Tammie T Coban Akdemir Zeynep H ZH Telegrafi Aida A Zackai Elaine H EH Begtrup Amber A Song Xiaofei X Toutain Annick A Wentzensen Ingrid M IM Odent Sylvie S Bonneau Dominique D Latypova Xénia X Deb Wallid W Redon Sylvia S Bilan Frédéric F Legendre Marine M Troyer Caitlin C Whitlock Kerri K Caluseriu Oana O Murphree Marine I MI Pichurin Pavel N PN Agre Katherine K Gavrilova Ralitza R Rinne Tuula T Park Meredith M Shain Catherine C Heinzen Erin L EL Xiao Rui R Amiel Jeanne J Lyonnet Stanislas S Isidor Bertrand B Biesecker Leslie G LG Lowenstein Dan D Posey Jennifer E JE Denommé-Pichon Anne-Sophie AS Férec Claude C Yang Xiang-Jiao XJ Rosenfeld Jill A JA Gilbert-Dussardier Brigitte B Audebert-Bellanger Séverine S Redon Richard R Stessman Holly A F HAF Nellaker Christoffer C Yang Yaping Y Lupski James R JR Goldstein David B DB Eichler Evan E EE Bolduc Francois F Bézieau Stéphane S Küry Sébastien S Campeau Philippe M PM

American journal of human genetics 20190228 3

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 collabora ...[more]

PMID: 30827496

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Similar Datasets

Novel Missense Variants in ADAT3 as a Cause of Syndromic Intellectual Disability.
| S-EPMC6824885 | biostudies-literature

POGZ truncating alleles cause syndromic intellectual disability.
| S-EPMC4702300 | biostudies-literature

NONO mutations cause syndromic intellectual disability and inhibitory synaptic defects
2015-09-02 | E-MTAB-2895 | biostudies-arrayexpress

NONO mutations cause syndromic intellectual disability and inhibitory synaptic defects
2015-09-02 | E-MTAB-2894 | biostudies-arrayexpress

Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation.
| S-EPMC5223032 | biostudies-literature

Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability.
| S-EPMC7269600 | biostudies-literature

Missense NAA20 variants impairing the NatB protein N-terminal acetyltransferase cause autosomal recessive developmental delay, intellectual disability, and microcephaly.
| S-EPMC8553619 | biostudies-literature

Dominant mutations in KAT6A cause intellectual disability with recognizable syndromic features.
| S-EPMC4375419 | biostudies-literature

Dominant β-catenin mutations cause intellectual disability with recognizable syndromic features.
| S-EPMC3973091 | biostudies-literature

Heterozygous variants in SPTBN1 cause intellectual disability and autism.
| S-EPMC11182376 | biostudies-literature