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

2019-03-07

Cogné, Benjamin

Ehresmann, Sophie

Beauregard-Lacroix, Eliane

Rousseau, Justine

Besnard, Thomas

Garcia, Thomas

Petrovski, Slavé

Avni, Shiri

McWalter, Kirsty

Blackburn, Patrick R

Sanders, Stephan J

Picard, Arnaud

Busk, Øyvind L

Punetha, Jaya

Pfundt, Rolph

Lindstrand, Anna

Nordgren, Ann

Kalb, Fayth

Desai, Megha

Ebanks, Ashley Harmon

Jhangiani, Shalini N

Song, Xiaofei

Dewan, Tammie

Coban Akdemir, Zeynep H

Telegrafi, Aida

Zackai, Elaine H

Begtrup, Amber

Toutain, Annick

Wentzensen, Ingrid M

Odent, Sylvie

Bonneau, Dominique

Latypova, Xénia

Deb, Wallid

Redon, Sylvia

Bilan, Frédéric

Legendre, Marine

Agre, Katherine

Troyer, Caitlin

Whitlock, Kerri

Caluseriu, Oana

Murphree, Marine I

Pichurin, Pavel N

Gavrilova, Ralitza

Rinne, Tuula

Park, Meredith

Shain, Catherine

Heinzen, Erin L

Xiao, Rui

Amiel, Jeanne

Lyonnet, Stanislas

Isidor, Bertrand

Yang, Xiang-Jiao

Biesecker, Leslie G

Lowenstein, Dan

Posey, Jennifer E

Denommé-Pichon, Anne-Sophie

Férec, Claude

Rosenfeld, Jill A

Gilbert-Dussardier, Brigitte

Audebert-Bellanger, Séverine

Redon, Richard

Stessman, Holly A F

Nellaker, Christoffer

Yang, Yaping

Lupski, James R

Goldstein, David B

Uguen, Kévin

Eichler, Evan E

Bolduc, Francois

Bézieau, Stéphane

Küry, Sébastien

Campeau, Philippe M

Harris, Jacqueline

Cohen, Julie S

Blyth, Moira

Lehman, Anna

Berg, Jonathan

Li, Mindy H

Kini, Usha

Joss, Shelagh

von der Lippe, Charlotte

Gordon, Christopher T

Humberson, Jennifer B

Robak, Laurie

Scott, Daryl A

Sutton, Vernon R

Skraban, Cara M

Johnston, Jennifer J

Poduri, Annapurna

Nordenskjöld, Magnus

Shashi, Vandana

Gerkes, Erica H

Bongers, Ernie M H F

Gilissen, Christian

Zarate, Yuri A

Kvarnung, Malin

Lally, Kevin P

Kulch, Peggy A

Daniels, Brina

Hernandez-Garcia, Andres

Stong, Nicholas

McGaughran, Julie

Retterer, Kyle

Tveten, Kristian

Sullivan, Jennifer

Geisheker, Madeleine R

Stray-Pedersen, Asbjorg

Tarpinian, Jennifer M

Klee, Eric W

Sapp, Julie C

Zyskind, Jacob

Holla, Øystein L

Bedoukian, Emma

Filippini, Francesca

Guimier, Anne

TRRAP

autism spectrum disorder

congenital malformations

de novo variants

histone acetylation

intellectual disability

neurodevelopmental disorders

Journal Article

0000-0002-1527-961X

10.1016/j.ajhg.2019.01.010

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.

link

American journal of human genetics 2019; 104(3): 530-541

American journal of human genetics