Abstract
Tatton-Brown-Rahman (TBRS) syndrome is a recently described overgrowth syndrome caused by loss of function variants in the DNMT3A gene. This gene encodes for a DNA methyltransferase 3 alpha, which is involved in epigenetic regulation, especially during embryonic development. Somatic variants in DNMT3A have been widely studied in different types of tumors, including acute myeloid leukemia, hematopoietic, and lymphoid cancers. Germline gain-of-function variants in this gene have been recently implicated in microcephalic dwarfism. Common clinical features of patients with TBRS include tall stature, macrocephaly, intellectual disability (ID), and a distinctive facial appearance. Differential diagnosis of TBRS comprises Sotos, Weaver, and Malan Syndromes. The majority of these disorders present other clinical features with a high clinical overlap, making necessary a molecular confirmation of the clinical diagnosis. We here describe seven new patients with variants in DNMT3A, four of them with neuropsychiatric disorders, including schizophrenia and psychotic behavior. In addition, one of the patients has developed a brain tumor in adulthood. This patient has also cerebral atrophy, aggressive behavior, ID, and abnormal facial features. Clinical evaluation of this group of patients should include a complete neuropsychiatric assessment together with psychological support in order to detect and manage abnormal behaviors such as aggressiveness, impulsivity, and attention deficit-hyperactivity disorder. TBRS should be suspected in patients with overgrowth, ID, tall stature, and macrocephaly, who also have some neuropsychiatric disorders without any genetic defects in the commonest overgrowth disorders. Molecular confirmation in these patients is mandatory.
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References
Lapunzina P. Risk of tumorigenesis in overgrowth syndromes: a comprehensive review. Am J Med Genet C Semin Med Genet. 2005;137C:53–71.
Tatton-Brown K, Seal S, Ruark E, Harmer J, Ramsay E, Del Vecchio Duarte S, et al. Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability. Nat Genet. 2014;46:385–8.
Lemire G, Gauthier J, Soucy JF, Delrue MA. A case of familial transmission of the newly described DNMT3A-overgrowth syndrome. Am J Med Genet Part A. 2017;173:1887–90.
Lyko F. The DNA methyltransferase family: a versatile toolkit for epigenetic regulation. Nat Rev Genet. 2018;19:81–92.
Rinaldi L, Datta D, Serrat J, Morey L, Solanas G, Avgustinova A, et al. Dnmt3a and Dnmt3b associate with enhancers to regulate human epidermal stem cell homeostasis. Cell Stem Cell. 2016;19:491–501.
Melberg A, Hetta J, Dahl N, Nennesmo I, Bengtsson M, Wibom R, et al. Autosomal dominant cerebellar ataxia deafness and narcolepsy. J Neurol Sci. 1995;134:119–29.
Winkelmann J, Lin L, Schormair B, Kornum BR, Faraco J, Plazzi G, et al. Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy. Hum Mol Genet. 2012;21:2205–10.
Klein CJ, Botuyan MV, Wu Y, Ward CJ, Nicholson GA, Hammans S, et al. Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss. Nat Genet. 2011;43:595–600.
Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell. 1999;99:247–57.
Tatton-Brown K, Zachariou A, Loveday C, Renwick A, Mahamdallie S, Aksglaede L, et al. The tatton-brown-rahman syndrome: a clinical study of 55 individuals with de novo constitutive DNMT3A variants. Wellcome Open Res. 2018;3:46.
Okamoto N, Toribe Y, Shimojima K, Yamamoto T. Tatton-Brown-Rahman syndrome due to 2p23 microdeletion. Am J Med Genet Part A. 2016;170A:1339–42.
Ley TJ, Ding L, Walter MJ, McLellan MD, Lamprecht T, Larson DE, et al. DNMT3A mutations in acute myeloid leukemia. New Engl J Med. 2010;363:2424–33.
Yamashita Y, Yuan J, Suetake I, Suzuki H, Ishikawa Y, Choi YL, et al. Array-based genomic resequencing of human leukemia. Oncogene. 2010;29:3723–31.
Emperle M, Rajavelu A, Kunert S, Arimondo PB, Reinhardt R, Jurkowska RZ, et al. The DNMT3A R882H mutant displays altered flanking sequence preferences. Nucleic acids Res. 2018;46:3130–9.
Hollink I, van den Ouweland AMW, Beverloo HB, Arentsen-Peters S, Zwaan CM, Wagner A. Acute myeloid leukaemia in a case with Tatton-Brown-Rahman syndrome: the peculiar DNMT3A R882 mutation. J Med Genet. 2017;54:805–8.
Shen W, Heeley JM, Carlston CM, Acuna-Hidalgo R, Nillesen WM, Dent KM, et al. The spectrum of DNMT3A variants in Tatton-Brown-Rahman syndrome overlaps with that in hematologic malignancies. Am J Med Genet Part A. 2017;173:3022–8.
Middleton FA, Mirnics K, Pierri JN, Lewis DA, Levitt P. Gene expression profiling reveals alterations of specific metabolic pathways in schizophrenia. J Neurosci. 2002;22:2718–29.
Saradalekshmi KR, Neetha NV, Sathyan S, Nair IV, Nair CM, Banerjee M. DNA methyl transferase (DNMT) gene polymorphisms could be a primary event in epigenetic susceptibility to schizophrenia. PloS ONE. 2014;9:e98182
Zhubi A, Veldic M, Puri NV, Kadriu B, Caruncho H, Loza I, et al. An upregulation of DNA-methyltransferase 1 and 3a expressed in telencephalic GABAergic neurons of schizophrenia patients is also detected in peripheral blood lymphocytes. Schizophr Res. 2009;111:115–22.
Langmead B, Salzberg SL. Fast gapped-read alignment with Bowtie 2. Nat Methods. 2012;9:357–9.
McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, et al. The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20:1297–303.
Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38:e164.
Liu X, Wu C, Li C, Boerwinkle E. dbNSFPv3.0: a one-stop database of functional predictions and annotations for human nonsynonymous and splice-site SNVs. Hum Mutat. 2016;37:235–41.
Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–91.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.
Cancer Genome Atlas Research N. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474:609–15.
Fickie MR, Lapunzina P, Gentile JK, Tolkoff-Rubin N, Kroshinsky D, Galan E, et al. Adults with Sotos syndrome: review of 21 adults with molecularly confirmed NSD1 alterations, including a detailed case report of the oldest person. Am J Med Genet Part A. 2011;155A:2105–11.
Tatton-Brown K, Murray A, Hanks S, Douglas J, Armstrong R, Banka S, et al. Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype. Am J Med Genet Part A. 2013;161A:2972–80.
Akawi N, Ben-Salem S, Lahti L, Partanen J, Ali BR, Al-Gazali L. A recessive syndrome of intellectual disability, moderate overgrowth, and renal dysplasia predisposing to Wilms tumor is caused by a mutation in FIBP gene. Am J Med Genet Part A. 2016;170:2111–8.
Luscan A, Laurendeau I, Malan V, Francannet C, Odent S, Giuliano F, et al. Mutations in SETD2 cause a novel overgrowth condition. J Med Genet. 2014;51:512–7.
Soellner L, Begemann M, Mackay DJ, Gronskov K, Tumer Z, Maher ER, et al. Recent advances in imprinting disorders. Clin Genet. 2017;91:3–13.
Heyn P, Logan CV, Fluteau A, Challis RC, Auchynnikava T, Martin CA, et al. Gain-of-function DNMT3A mutations cause microcephalic dwarfism and hypermethylation of Polycomb-regulated regions. Nat Genet. 2018;51:96–105.
Faludi G, Mirnics K. Synaptic changes in the brain of subjects with schizophrenia. Int J Dev Neurosci. 2011;29:305–9.
Arion D, Unger T, Lewis DA, Levitt P, Mirnics K. Molecular evidence for increased expression of genes related to immune and chaperone function in the prefrontal cortex in schizophrenia. Biol Psychiatry. 2007;62:711–21.
Hashimoto T, Arion D, Unger T, Maldonado-Aviles JG, Morris HM, Volk DW, et al. Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia. Mol psychiatry. 2008;13:147–61.
Hakak Y, Walker JR, Li C, Wong WH, Davis KL, Buxbaum JD, et al. Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia. Proc Natl Acad Sci USA. 2001;98:4746–51.
Guidotti A, Ruzicka W, Grayson DR, Veldic M, Pinna G, Davis JM, et al. S-adenosyl methionine and DNA methyltransferase-1 mRNA overexpression in psychosis. Neuroreport. 2007;18:57–60.
Karen C, Rajan KE. Social behaviour and epigenetic status in adolescent and adult rats: the contribution of early-life stressful social experience. Cell Mol Neurobiol. 2019;39:371–85.
Xin B, Cruz Marino T, Szekely J, Leblanc J, Cechner K, Sency V, et al. Novel DNMT3A germline mutations are associated with inherited Tatton-Brown-Rahman syndrome. Clin Genet. 2017;91:623–8.
Yang Y, Muzny DM, Xia F, Niu Z, Person R, Ding Y, et al. Molecular findings among patients referred for clinical whole-exome sequencing. JAMA. 2014;312:1870–9.
Yang Y, Muzny DM, Reid JG, Bainbridge MN, Willis A, Ward PA, et al. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. New Engl J Med. 2013;369:1502–11.
Tarailo-Graovac M, Shyr C, Ross CJ, Horvath GA, Salvarinova R, Ye XC, et al. Exome sequencing and the management of neurometabolic disorders. New Engl J Med. 2016;374:2246–55.
Posey JE, Harel T, Liu P, Rosenfeld JA, James RA, Coban Akdemir ZH, et al. Resolution of disease phenotypes resulting from multilocus genomic variation. New Engl J Med. 2017;376:21–31.
Acknowledgements
We would like to thank all the families and professionals who participate in the SOGRI consortium registry initiative. This project was supported by ISCII, FEDER funds grant: FIS-PI15/01481.
The SOGRI Consortium:
Alberto L. Rosa1,2, Aleixandre Blanquer1,2, Alfredo García Alix1,2, Alfredo Santana1,2, Alicia Delicado1,2, Almudena Alonso1,2, Amaya Rodríguez1,2, Amparo Sanchis1,2, Ana Moreno1,2, Ana Patiño García1,2, Ana Vega1,2, Analía Bredani1,2, Andrea Paula Solari1,2, Andrea Villavicencio1,2, Angelina Acosta1,2, Aníbal Nieto1,2, Anna María Cueto González1,2, Antonio Baldellon1,2, Antonio González Meneses1,2, Antonio Martínez Carrascal1,2, Aranzazu Díaz de Bustamante1,2, Arteche Ocasar1,2, Blanca Gener1,2, Blasco González1,2, Boris Groisman1,2, Bradford Coffee1,2, Carlos Alcalde Martín1,2, Carmen Aragón Fernández1,2, Carmen Benito1,2, Carmen González Armengod1,2, Carmen Martín Seisdedos1,2, Carmen Roche1,2, Claudia Arberas1,2, Claudia Perandones1,2, Claudia Toledo Pacheco1,2, Claudio Contessotto1,2, Cristina Olivas1,2, Daniel Armenta1,2, Denise Cavalcanti1,2, Dolores Elorza1,2, Eduardo Castilla1,2, Elena Zamora1,2, Elisa Zambrano1,2, Elisabeth Steichen1,2, Encarna Guillén Navarro1,2, Enrique Caro Cruz1,2, Enrique Galán Gómez1,2, Enriqueta Román1,2, Ernesto Goldschmidt1,2, Esteban Marfil1,2, Esther Gean1,2, Eugenia Antolín1,2, F. Javier Gascón Jiménez1,2, Fco. Javier Martínez Sarries1,2, Feliciano Ramos1,2, Fermina López Grondona1,2, Fernández Córdoba1,2, Fernando Santos1,2, Fernando Vargas1,2, Francisco Martínez1,2, Giovannucci Uzielli1,2, Gloria Gacio1,2, Graciela Mercado1,2, Hamilton Cassinelli1,2, Ieda Orioli1,2, Ignacio Arroyo1,2, Ignacio Díez López1,2, Ignacio Onsurbe Ramírez1,2, Ignacio Pascual Castroviejo1,2, Ignacio Pascual Pascual1,2, Ignacio Vázquez Rio1,2, Inés Bueno1,2, Isabel Espejo Portero1,2, Isabel Lorda Sánchez1,2, Jaime Sánchez del Pozo1,2, Jaume Campistol1,2, Javier Arcas1,2, Javier Fernández1,2, Javier García Planells1,2, Javier López Pisón1,2, Jesús Barreiro1,2, Jesús del Valle Núñez1,2, Joaquín Fernández Toral1,2, Joaquín Ramírez1,2, Jordi Rosell1,2, Jorge Vilaplana1,2, José Carlos Cabral de Almeida1,2, José Ignacio Labarta1,2, José L. Herranz1,2, José Luis Fernández Luna1,2, José Luis Fuster1,2, José M. Díaz1,2, José M. Gairi1,2, José Miguel García Sagredo1,2, Juan A. Piñero1,2, Juan Carlos López Gutiérrez1,2, Juan Manuel Fernández1,2, Juan P. López Siguero1,2, Juan Tovar1,2, Judith Armstrong1,2, Julián Lara1,2, Laura Rodríguez Leandro Soriano1,2, Leila Cardoso1,2, Leonor Arranz1,2, Liliana De Alba1,2, Loreta Cimbalistiene1,2, Loreto Martorell1,2, Luis González Gutiérrez Solana1,2, Luis Pérez Jurado1,2, M Asunción López Ariztegui1,2, M. Antonia Molina1,2, M. Cruz García1,2, M. Ferrer Lozano1,2, M. Jesús Alija Merillas1,2, M. Luisa Martínez-Frías1,2, M. Rocío Jadraque1,2, Mª Asunción García Pérez1,2, Mª Montserrat Rodríguez Pedreira1,2, Mª Nieves Martínez Guardia1,2, Mª Pilar Ribate1,2, Mª Teresa González López1,2, Mª Teresa Moral Pumarega1,2, Mabel Segovia1,2, Macarena Lizama1,2, Manuel J. Lorente1,2, Manuel Pombo1,2, Margarita Martínez1,2, Margarita Tabernero1,2, María Antonia Ramos1,2, María Ballesta1,2, María Belar1,2, María Jesús Lautre1,2, Marta Cruz1,2, Mercedes Artigas1,2, Mercedes Villanueva1,2, Meritxell Torrabías1,2, Miguel del Campo1,2, Miguel Tomás Vila1,2, Miguel Urioste1,2, Mónica Rosello1,2, Nazneen Rahman1,2, Nik Kantaputra1,2, Pablo Prieto Matos1,2, Paloma Dorao1,2, Paula Casano1,2, Paula Lalaguna Mallada1,2, Pedro Olivares1,2, Pilar Tirado1,2, Pricila Bernardi1,2, Rafael Camino León1,2, Ramón Cañete1,2, Ramón Gaztañaga1,2, Ramón Velazquez1,2, Ramón Vidal Samahuja1,2, Raquel Pérez Delgado1,2, Raquel Sáez Villaverde1,2, Ricardo Gracia1,2, Richard Scott1,2, Rita Valdez1,2, Rosa Arteaga1,2, Rosa Cedeño1,2, Rosario Cazorla1,2, Rosario Marín Iglesias1,2, Rubén Bronberg1,2, Salvador Climent1,2, Santiago Conde Barreiro1,2, Seema Kapoor1,2, Selma Vázquez Martín1,2, Sixto García Miñaur1,2, Soledad Kleppe1,2, Sonia Santillán1,2, Teresa Calvo1,2, Teresa Vendrell1,2, V. López González1,2, Vanesa López1,2, Vanesa Lotersztein1,2, Vanesa Méndez1,2, Vicente Albiach1,2, Víctor M. Navas López1,2, Virginia Soler1,2, Viviana Cosentino, Yoko Aoki1,2
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Tenorio, J., Alarcón, P., Arias, P. et al. Further delineation of neuropsychiatric findings in Tatton-Brown-Rahman syndrome due to disease-causing variants in DNMT3A: seven new patients. Eur J Hum Genet 28, 469–479 (2020). https://doi.org/10.1038/s41431-019-0485-3
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DOI: https://doi.org/10.1038/s41431-019-0485-3
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