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Abstract
Background Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879), also known as DNA methyltransferase 3 alpha (DNMT3A)-overgrowth syndrome (DOS), was first described by Tatton-Brown in 2014. This syndrome is characterised by overgrowth, intellectual disability and distinctive facial features and is the consequence of germline loss-of-function variants in DNMT3A, which encodes a DNA methyltransferase involved in epigenetic regulation. Somatic variants of DNMT3A are frequently observed in haematological malignancies, including acute myeloid leukaemia (AML). To date, 100 individuals with TBRS with de novo germline variants have been described. We aimed to further characterise this disorder clinically and at the molecular level in a nationwide series of 24 French patients and to investigate the correlation between the severity of intellectual disability and the type of variant.
Methods We collected genetic and medical information from 24 individuals with TBRS using a questionnaire released through the French National AnDDI-Rares Network.
Results Here, we describe the first nationwide French cohort of 24 individuals with germline likely pathogenic/pathogenic variants in DNMT3A, including 17 novel variants. We confirmed that the main phenotypic features were intellectual disability (100% of individuals), distinctive facial features (96%) and overgrowth (87%). We highlighted novel clinical features, such as hypertrichosis, and further described the neurological features and EEG results.
Conclusion This study of a nationwide cohort of individuals with TBRS confirms previously published data and provides additional information and clarifies clinical features to facilitate diagnosis and improve care. This study adds value to the growing body of knowledge on TBRS and broadens its clinical and molecular spectrum.
- genetic diseases, inborn
- exome sequencing
- genetics, medical
- loss of function mutation
- mental disorders
Data availability statement
Data sharing not applicable as no datasets generated and/or analysed for this study.
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Data availability statement
Data sharing not applicable as no datasets generated and/or analysed for this study.
Footnotes
LL and CB are joint senior authors.
X @NicoChatron
HT and TA contributed equally.
LL and CB contributed equally.
Contributors CB is the guarantor. LL, MR and CB conceptualised and designed the study. CB collected the samples. LL, MR, ER, JW, SZ, BL, DG, MWi, CC, ES, SB, MV, MN, LR, EP, PE, LF, J-LA, ML, CQ, SO, CM, AA, SJ, AG, ADSM, SN, MDe, CM and VC-D clinically characterised the individuals. TA, CP, ND, JMR, MWa, MB, AB, VR, MM, MDi, GV, AP, BG, BC, GL, NCh, MT, FT-M-T, VD, MF, NCo, BK, SR, EB, GB, TH, AO and CB performed the genetic studies and data analysis and interpretation. TH, DC, FL, GN and CC generated DNA methylation data from patient 13 and interpreted the DNMT3A episignature. HT collected the clinical data. TA and CB collected the molecular data. HT wrote the first draft of the manuscript. TA, ER, JMR, LL and CB revised the manuscript. CB supervised the project and edited the manuscript. All the authors critically revised and approved the final manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Disclaimer The sponsor was CHRU de Nancy (Direction de la Recherche et de l’Innovation).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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