Abstract
BRAT1 biallelic variants are associated with rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL), and neurodevelopmental disorder associating cerebellar atrophy with or without seizures syndrome (NEDCAS). To date, forty individuals have been reported in the literature. We collected clinical and molecular data from 57 additional cases allowing us to study a large cohort of 97 individuals and draw phenotype-genotype correlations. Fifty-nine individuals presented with BRAT1-related RMFSL phenotype. Most of them had no psychomotor acquisition (100%), epilepsy (100%), microcephaly (91%), limb rigidity (93%), and died prematurely (93%). Thirty-eight individuals presented a non-lethal phenotype of BRAT1-related NEDCAS phenotype. Seventy-six percent of the patients in this group were able to walk and 68% were able to say at least a few words. Most of them had cerebellar ataxia (82%), axial hypotonia (79%) and cerebellar atrophy (100%). Genotype-phenotype correlations in our cohort revealed that biallelic nonsense, frameshift or inframe deletion/insertion variants result in the severe BRAT1-related RMFSL phenotype (46/46; 100%). In contrast, genotypes with at least one missense were more likely associated with NEDCAS (28/34; 82%). The phenotype of patients carrying splice variants was variable: 41% presented with RMFSL (7/17) and 59% with NEDCAS (10/17).
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Data availability
The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
The authors would like to thank the families for their participation in this study. Funding: SS received funding from National Institute of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS) (K23NS119666). FSA acknowledges the support of King Salman Center for Disability Research through Research Group no RG-2022-011.
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CE, SV, GD, RM collected clinical and molecular data. CE, JP analyzed and interpreted data and wrote the manuscript. JP, LVM designed the study. SV, RM, AA, EA, FSA, VB, IB, MB-L, EB, IB, EB-B, A-LB, AB, DKB, CC, MRC, M-CC, CC, OD, VD, A-SD-P, MCDG, MD-F, HE, KC, MG, JGG, DH, JG, AG, FLH, HH, MI, RK, BK, EGK, DK, PK, KK, DL, LM, CM, DM-R, LN, SO, CO, JNP, LP, LP, CP, GP, CP, AP, MR, CR, VS, IS, AS, SS, RS, PS, EMV, PV, LV, AV, JW, MW, MSZ, FZ, GL, VRY, MM, FH-G, MB, FA, HG, CW, AN, MT, DS, YM, KK, CS, VC, MZ, LVM, LB characterized the clinical and molecular features of the disease. All the authors edited or commented the manuscript.
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Individuals were referred by clinical geneticists for genetic testing as part of routine clinical care. All patients enrolled and/or their legal representative have signed informed consent for use of data and/or photographs. This study has been performed in accordance with the Declaration of Helsinki.
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Engel, C., Valence, S., Delplancq, G. et al. BRAT1–related disorders: phenotypic spectrum and phenotype-genotype correlations from 97 patients. Eur J Hum Genet 31, 1023–1031 (2023). https://doi.org/10.1038/s41431-023-01410-z
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DOI: https://doi.org/10.1038/s41431-023-01410-z
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