BRAT1 mutations present with a spectrum of clinical severity

Abstract

Mutations in BRAT1, encoding BRCA1-associated ATM activator 1, are associated with a severe phenotype known as rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL; OMIM # 614498), characterized by intractable seizures, hypertonia, autonomic instability, and early death. We expand the phenotypic spectrum of BRAT1 related disorders by reporting on four individuals with various BRAT1 mutations resulting in clinical severity that is either mild or moderate compared to the severe phenotype seen in RMFSL. Representing mild severity are three individuals (Patients 1–3), who are girls (including two sisters, Patients 1–2) between 4–10 years old, with subtle dysmorphisms, intellectual disability, ataxia or dyspraxia, and cerebellar atrophy on brain MRI; additionally, Patient 3 has well-controlled epilepsy and microcephaly. Representing moderate severity is a 15 month old boy (Patient 4) with severe global developmental delay, refractory epilepsy, microcephaly, spasticity, hyperkinetic movements, dysautonomia, and chronic lung disease. In contrast to RMFSL, his seizure onset occurred later at 4 months of age, and he is still alive. All four of the individuals have compound heterozygous BRAT1 mutations discovered via whole exome sequencing: c.638dupA (p.Val214Glyfs*189); c.803+1G>C (splice site mutation) in Patients 1–2; c.638dupA (p.Val214Glyfs*189); c.419T>C (p.Leu140Pro) in Patient 3; and c.171delG (p.Glu57Aspfs*7); c.419T>C (p.Leu140Pro) in Patient 4. Only the c.638dupA (p.Val214Glyfs*189) mutation has been previously reported in association with RMFSL. These patients illustrate that, compared with RMFSL, BRAT1 mutations can result in both moderately severe presentations evident by later-onset epilepsy and survival past infancy, as well as milder presentations that include intellectual disability, ataxia/dyspraxia, and cerebellar atrophy.

BRAT1‐associated neurodegeneration: Intra‐familial phenotypic differences in siblings

“…However, recent descriptions expand the clinical spectrum, with less severe phenotypes reported in six unrelated children [Hanes et al, ; Fernández‐Jaén et al, ; Horn et al, ; Mundy et al, ; Srivastava et al, ]. Patients with intellectual disability, but no seizures or progressive phenotype have been described [Srivastava et al, ]. Here we report siblings with compound heterozygous truncating mutations in BRAT1 , demonstrating intra‐familial clinical heterogeneity and review the broadening phenotype attributed to dysfunction of BRAT1 .…”

“…A total of 13 patients and families, including the family described here, carrying 15 different mutations in BRAT1 have been identified (Table , Fig. B) [Puffenberger et al, ; Saunders et al, ; Saitsu et al, ; Hanes et al, ; Straussberg et al, , van de Pol et al, ; Fernández‐Jaén et al, ; Horn et al, ; Mundy et al, ; Srivastava et al, ]. Seven mutations including those reported here are either frameshifts or stop‐gains leading to premature termination of protein translation.…”

“…There are reports of seven unrelated children with compound heterozygous mutations in BRAT1 surviving into later childhood, thus expanding the classical phenotype to include patients with survival beyond 2 years [Hanes et al, ; Fernández‐Jaén et al, ; Horn et al, ; Mundy et al, ; Srivastava et al, ]. In most cases, onset of post‐natal microcephaly and neuromotor features occurred before 6 months, however, some neurodevelopmental progress and survival beyond 4 years was observed in all cases.…”

“…The disorder typically manifests as a severe phenotype including neonatal microcephaly, hypertonia, and refractory epilepsy with premature death by 2 years and, in the majority, by 6 months [Puffenberger et al, ; Saunders et al, ; Saitsu et al, ; Straussberg et al, ; van de Pol et al, ]. However, recent descriptions expand the clinical spectrum, with less severe phenotypes reported in six unrelated children [Hanes et al, ; Fernández‐Jaén et al, ; Horn et al, ; Mundy et al, ; Srivastava et al, ]. Patients with intellectual disability, but no seizures or progressive phenotype have been described [Srivastava et al, ].…”

Epileptic Encephalopathy Due to BRAT1 Pathogenic Variants

“…In fact, in addition to the severe lethal form known as RMFSL, both mild and moderate forms of BRAT1 -related disorders may exist. Mildly affected individuals may present with intellectual disability without epilepsy/seizures, ataxia, cerebellar atrophy, and continued survival through late childhood [4]. Given the phenotypic differences seen with siblings, intrafamilial variability can occur.…”