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 language | English |
|---|---|
| Pages (from-to) | 530-541 |
| Number of pages | 12 |
| Journal | American Journal of Human Genetics |
| Volume | 104 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 7 2019 |
Bibliographical note
Publisher Copyright:© 2019 American Society of Human Genetics
Funding
We would like to thank all families for participating in this study. This work was supported in part by grants from: the French Ministry of Health and the Health Regional Agency from Poitou-Charentes ( HUGODIMS , 2013, RC14_0107 ) to S.B.; the National Institute of Neurological Disorders and Stroke ( The Epilepsy Phenome/Genome Project NS053998 ; Epi4K NS077364 , NS077274 , NS077303 , and NS077276 ) to D.L. and D.B.G.; the National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development grant ( HD064667 ) to D.A.S.; NINDS R35 NS105078 to J.R.L.; the National Human Genome Research Institute (NHGRI) and National Heart, Lung, and Blood Institute (NHLBI) to the Baylor-Hopkins Center for Mendelian Genomics ( UM1 HG006542 ); NHGRI K08 HG008986 to J.E.P.; the Duke Genome Sequencing Clinic to V.S. and J.S.; the intramural research program of the NHGRI (grant HG200328 12 ) to L.G.B., J.J.J., and J.C.S.; the US National Institute of Mental Health grant R01MH101221 to E.E.E.; the Kids Brain Health Network and Dart NeuroScience to F.B.; and Mining for Miracles , British Columbia Children’s Hospital Foundation , and Genome British Columbia to the CAUSES Study. We thank the Canadian Institutes of Health Research ( CIHR ) and Fonds de la recherche en santé du Québec ( FRSQ ) for clinician-scientist awards to P.M.C.; and the Mayo Clinic Center for Individualized Medicine (CIM) for supporting this research through the CIM Investigative and Functional Genomics Program . We are grateful to the members of the Canadian Center for Computational Genomics and the McGill University and Génome Québec Innovation Center for their help in bioinformatics analysis. We would like to thank all families for participating in this study. This work was supported in part by grants from: the French Ministry of Health and the Health Regional Agency from Poitou-Charentes (HUGODIMS, 2013, RC14_0107) to S.B.; the National Institute of Neurological Disorders and Stroke (The Epilepsy Phenome/Genome Project NS053998; Epi4K NS077364, NS077274, NS077303, and NS077276) to D.L. and D.B.G.; the National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development grant (HD064667) to D.A.S.; NINDS R35 NS105078 to J.R.L.; the National Human Genome Research Institute (NHGRI) and National Heart, Lung, and Blood Institute (NHLBI) to the Baylor-Hopkins Center for Mendelian Genomics (UM1 HG006542); NHGRI K08 HG008986 to J.E.P.; the Duke Genome Sequencing Clinic to V.S. and J.S.; the intramural research program of the NHGRI (grant HG200328 12) to L.G.B., J.J.J., and J.C.S.; the US National Institute of Mental Health grant R01MH101221 to E.E.E.; the Kids Brain Health Network and Dart NeuroScience to F.B.; and Mining for Miracles, British Columbia Children's Hospital Foundation, and Genome British Columbia to the CAUSES Study. We thank the Canadian Institutes of Health Research (CIHR) and Fonds de la recherche en sant? du Qu?bec (FRSQ) for clinician-scientist awards to P.M.C.; and the Mayo Clinic Center for Individualized Medicine (CIM) for supporting this research through the CIM Investigative and Functional Genomics Program. We are grateful to the members of the Canadian Center for Computational Genomics and the McGill University and G?nome Qu?bec Innovation Center for their help in bioinformatics analysis. We would like to thank all families for participating in this study. This work was supported in part by grants from: the French Ministry of Health and the Health Regional Agency from Poitou-Charentes (HUGODIMS, 2013, RC14_0107) to S.B.; the National Institute of Neurological Disorders and Stroke (The Epilepsy Phenome/Genome Project NS053998; Epi4K NS077364, NS077274, NS077303, and NS077276) to D.L. and D.B.G.; the National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development grant (HD064667) to D.A.S.; NINDS R35 NS105078 to J.R.L.; the National Human Genome Research Institute (NHGRI) and National Heart, Lung, and Blood Institute (NHLBI) to the Baylor-Hopkins Center for Mendelian Genomics (UM1 HG006542); NHGRI K08 HG008986 to J.E.P.; the Duke Genome Sequencing Clinic to V.S. and J.S.; the intramural research program of the NHGRI (grant HG200328 12) to L.G.B., J.J.J., and J.C.S.; the US National Institute of Mental Health grant R01MH101221 to E.E.E.; the Kids Brain Health Network and Dart NeuroScience to F.B.; and Mining for Miracles, British Columbia Children's Hospital Foundation, and Genome British Columbia to the CAUSES Study. We thank the Canadian Institutes of Health Research (CIHR) and Fonds de la recherche en santé du Québec (FRSQ) for clinician-scientist awards to P.M.C.; and the Mayo Clinic Center for Individualized Medicine (CIM) for supporting this research through the CIM Investigative and Functional Genomics Program. We are grateful to the members of the Canadian Center for Computational Genomics and the McGill University and Génome Québec Innovation Center for their help in bioinformatics analysis.
| Funders | Funder number |
|---|---|
| Mining for Miracles | |
| NIH National Institute of Child Health and Human Development National Center for Medical Rehabilitation Research | |
| Mayo Clinic Rochester | |
| British Columbia Children's Hospital Foundation | |
| Fonds de la recherche en sant? | |
| Fonds de Recherche du Québec-Santé | |
| Ministère des Affaires Sociales et de la Santé | |
| National Institutes of Health (NIH) | |
| Kids Brain Health Network | |
| McGill University | |
| National Heart, Lung, and Blood Institute (NHLBI) | |
| BC Children’s Hospital Foundation | |
| FRSQ | |
| Canadian Institutes of Health Research | |
| Genome British Columbia | |
| Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council | U01NS077274, U01NS077276, U01NS077364, U01NS077303, R35NS105078, U01NS053998 |
| National Institute of Mental Health | R01MH101221 |
| Baylor-Hopkins Center for Mendelian Genomics | UM1 HG006542, HG200328 12, K08 HG008986 |
| National Human Genome Research Institute | UM1HG006542, K08HG008986, ZIAHG200328 |
| National Institute of General Medical Sciences DP2GM119177 Sophie Dumont National Institute of General Medical Sciences | T32GM007266 |
| Eunice Kennedy Shriver National Institute of Child Health and Human Development | R01HD064667 |
| Tuscany Regional Health Agency | RC14_0107 |
Keywords
- TRRAP
- autism spectrum disorder
- congenital malformations
- de novo variants
- histone acetylation
- intellectual disability
- neurodevelopmental disorders
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)