BRAT1-related disorders: phenotypic spectrum and phenotype-genotype correlations from 97 patients

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).

Fig. 1. Brain magnetic resonance image (MRI) of individuals with biallelic BRAT1 variants.

A Patients with RMFSL (P1, P3, P4, P5, P25). Note cerebral atrophy and enlarged subarachnoid spaces on axial and sagittal planes. B Patients with NEDCAS (P32, P33, P35, P36). Note cerebellar atrophy on sagittal and coronal planes.

Fig. 2. Photographs of individuals with BRAT1-related disorders.

A Patients from RMFSL group. Coarse facies are noted without specific dysmorphic features. B Patients from NEDCAS group. A triangular face, a high nasal bridge and strabismus are noted in some patients.

Fig. 3. Graphical representation of BRAT1 variants (IBS 1.0.3).

Missense and in-frame deletions are above; nonsense, frameshift and splice variants are below. Variants in black were identified in patients with RMFSL phenotype, those in white in patients with NEDCAS. Each square represents a patient with a homozygous variant, each circle a patient with a heterozygous one. Note that all the patients with a homozygous loss-of function variant are presenting a RMFSL phenotype and that the only one patient with a homozygous missense variant and a severe phenotype may have a second associated etiology. NDFIP1, NEDD4 family interacting protein 1; HEAT1/HEAT2, protein tandem repeat structural motif found in the four proteins: Huntingtin, Elongation factor 3 (EF3), protein phosphatase 2 A (PP2A) and TOR1.

Fig. 4. Genotypes of patients with RMFSL and NEDCAS phenotypes.

Are considered in the groups “at least 1 splice variant” or “deletion/inframe insertion” the patients having respectively a splice variant or an inframe deletion/insertion in trans of any other variant (except a missense). Note that the majority of patients with NEDCAS presenting with at least one missense variant and that none of them are carrying two nonsense or frameshift variants. On the contrary, two third of the patients with RMFSL presenting with two frameshift, two nonsense or inframe deletion/duplication.

Fig. 5. Genotype-phenotype correlations for BRAT1 variants.

The percentage of patients with RMFSL are shown in black, and those with NEDCAS in grey. Note that all patients with two frameshift/nonsense or inframe insertions/deletions have an RMFSL phenotype, and that the majority of patients with at least one missense have a NEDCAS phenotype.