Centre de Génétique Humaine, Centre Hospitalier Régional Universitaire, Université de Franche-Comté, Besançon, France.
Service de Neurologie Pédiatrique, Hôpital Armand Trousseau, APHP Sorbonne Université, Paris, France.
Eur J Hum Genet. 2023 Sep;31(9):1023-1031. doi: 10.1038/s41431-023-01410-z. Epub 2023 Jun 21.
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).
BRAT1 双等位基因突变与僵硬和多灶性癫痫综合征、致死性新生儿（RMFSL）和神经发育障碍伴小脑萎缩伴或不伴癫痫综合征（NEDCAS）相关。迄今为止，文献中已报道了四十例。我们收集了 57 例额外病例的临床和分子数据，使我们能够研究一个由 97 例个体组成的大队列，并得出表型-基因型相关性。59 例个体表现出与 BRAT1 相关的 RMFSL 表型。他们大多数没有精神运动发育（100%）、癫痫（100%）、小头畸形（91%）、肢体僵硬（93%）和过早死亡（93%）。38 例个体表现出与 BRAT1 相关的 NEDCAS 表型非致死性。该组中有 76%的患者能够行走，68%的患者能够说至少几个字。他们大多数人有小脑共济失调（82%）、轴向张力减退（79%）和小脑萎缩（100%）。我们队列中的基因型-表型相关性表明，双等位基因无义、移码或内含子缺失/插入变异导致严重的 BRAT1 相关 RMFSL 表型（46/46；100%）。相比之下，至少有一种错义的基因型更可能与 NEDCAS 相关（28/34；82%）。携带剪接变异体的患者的表型是可变的：41%表现为 RMFSL（7/17），59%表现为 NEDCAS（10/17）。
