American journal of human genetics · 2019

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

СтатьяПоддержка NIH: внешняя программаResearch Support, N.I.H., IntramuralПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди

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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, Uguen Kévin, 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, Picard Arnaud, Busk Øyvind L, Punetha Jaya, Pfundt Rolph, Lindstrand Anna, Nordgren Ann, Kalb Fayth, Desai Megha, Ebanks Ashley Harmon, Jhangiani Shalini N, Dewan Tammie, Coban Akdemir Zeynep H, Telegrafi Aida, Zackai Elaine H, Begtrup Amber, Song Xiaofei, Toutain Annick, Wentzensen Ingrid M, Odent Sylvie, Bonneau Dominique, Latypova Xénia, Deb Wallid, CAUSES Study, Redon Sylvia, Bilan Frédéric, Legendre Marine, Troyer Caitlin, Whitlock Kerri, Caluseriu Oana, Murphree Marine I, Pichurin Pavel N, Agre Katherine, Gavrilova Ralitza, Rinne Tuula, Park Meredith, Shain Catherine, Heinzen Erin L, Xiao Rui, Amiel Jeanne, Lyonnet Stanislas, Isidor Bertrand, Biesecker Leslie G, Lowenstein Dan, Posey Jennifer E, Denommé-Pichon Anne-Sophie, Deciphering Developmental Disorders study, Férec Claude, Yang Xiang-Jiao, 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, Eichler Evan E, Bolduc Francois, Bézieau Stéphane, Küry Sébastien, Campeau Philippe M

Аннотация

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.

Предметные рубрики MeSH

Adaptor Proteins, Signal Transducing Adolescent Adult Amino Acid Sequence Autistic Disorder Child Child, Preschool Female Genetic Association Studies Humans Infant Intellectual Disability Male Mutation, Missense Nuclear Proteins Prognosis Sequence Homology Syndrome Young Adult

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

Ошибки и ограничения

Аннотация

Предметные рубрики MeSH