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

TitleMissense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability.
Publication TypeJournal Article
Year of Publication2019
AuthorsCogné, B, Ehresmann, S, Beauregard-Lacroix, E, Rousseau, J, Besnard, T, Garcia, T, Petrovski, S, Avni, S, McWalter, K, Blackburn, PR, Sanders, SJ, Uguen, K, Harris, J, Cohen, JS, Blyth, M, Lehman, A, Berg, J, Li, MH, Kini, U, Joss, S, von der Lippe, C, Gordon, CT, Humberson, JB, Robak, L, Scott, DA, Sutton, VR, Skraban, CM, Johnston, JJ, Poduri, A, Nordenskjöld, M, Shashi, V, Gerkes, EH, Bongers, EMHF, Gilissen, C, Zarate, YA, Kvarnung, M, Lally, KP, Kulch, PA, Daniels, B, Hernandez-Garcia, A, Stong, N, McGaughran, J, Retterer, K, Tveten, K, Sullivan, J, Geisheker, MR, Stray-Pedersen, A, Tarpinian, JM, Klee, EW, Sapp, JC, Zyskind, J, Holla, ØL, Bedoukian, E, Filippini, F, Guimier, A, Picard, A, Busk, ØL, Punetha, J, Pfundt, R, Lindstrand, A, Nordgren, A, Kalb, F, Desai, M, Ebanks, AHarmon, Jhangiani, SN, Dewan, T, Akdemir, ZHCoban, Telegrafi, A, Zackai, EH, Begtrup, A, Song, X, Toutain, A, Wentzensen, IM, Odent, S, Bonneau, D, Latypova, X, Deb, W, Redon, S, Bilan, F, Legendre, M, Troyer, C, Whitlock, K, Caluseriu, O, Murphree, MI, Pichurin, PN, Agre, K, Gavrilova, R, Rinne, T, Park, M, Shain, C, Heinzen, EL, Xiao, R, Amiel, J, Lyonnet, S, Isidor, B, Biesecker, LG, Lowenstein, D, Posey, JE, Denommé-Pichon, A-S, Férec, C, Yang, X-J, Rosenfeld, JA, Gilbert-Dussardier, B, Audebert-Bellanger, S, Redon, R, Stessman, HAF, Nellaker, C, Yang, Y, Lupski, JR, Goldstein, DB, Eichler, EE, Bolduc, F, Bézieau, S, Küry, S, Campeau, PM
Corporate AuthorsCAUSES Study, Deciphering Developmental Disorders study
JournalAm J Hum Genet
Date Published2019 Mar 07
KeywordsAdaptor 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

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.

Alternate JournalAm J Hum Genet
PubMed ID30827496
PubMed Central IDPMC6407527
Grant ListU54 HD083091 / HD / NICHD NIH HHS / United States
U01 NS077274 / NS / NINDS NIH HHS / United States
Z01 HG200328 / / Intramural NIH HHS / United States
R01 HD064667 / HD / NICHD NIH HHS / United States
/ CAPMC / CIHR / Canada
UM1 HG006542 / HG / NHGRI NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
K08 HG008986 / HG / NHGRI NIH HHS / United States
U01 NS053998 / NS / NINDS NIH HHS / United States
U01 NS077364 / NS / NINDS NIH HHS / United States
U01 NS077303 / NS / NINDS NIH HHS / United States
U54 HD086984 / HD / NICHD NIH HHS / United States
U01 NS077276 / NS / NINDS NIH HHS / United States
T32 GM007266 / GM / NIGMS NIH HHS / United States
MR/M014568/1 / MRC_ / Medical Research Council / United Kingdom
R01 MH101221 / MH / NIMH NIH HHS / United States

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