BRAT1

The BRAT1 gene, located on chromosome 7p22, encodes a protein crucial for the DNA damage response (DDR), which plays a key role in maintaining genomic stability. Mutations in BRAT1 impair this pathway, leading to a spectrum of neurological disorders, from severe conditions like Lethal Neonatal Rigidity and Multifocal Seizure Syndrome (RMFSL) to milder neurodevelopmental disorders. 

The BRAT1 protein interacts with ATM (Ataxia-Telangiectasia Mutated) to stabilize it after DNA damage, a vital process for proper cell-cycle regulation and DNA repair.

What is BRAT1? 

The BRAT1 gene, located on chromosome 7p22, encodes a protein involved in the DNA damage response (DDR), which is critical for maintaining genomic stability. 

The protein produced by the BRAT1 gene interacts with ATM (Ataxia-Telangiectasia Mutated) protein, helping to stabilize ATM after DNA damage occurs. This interaction is essential, ensuring proper cell-cycle regulation and DNA repair, which are vital for preventing genomic instability. 

BRAT1 may also play a role in cell growth and apoptosis.

Mutations in BRAT1 lead to a loss of protein function, which impairs the DDR pathway, contributing to various neurological disorders. These mutations disrupt normal cell processes, including cell proliferation, migration, and mitochondrial function, often leading to neuronal degeneration and developmental abnormalities. 

As a result, BRAT1 mutations are associated with a spectrum of conditions, ranging from severe, life-threatening disorders to milder neurodevelopmental disorders.

What is the DDR?

The DNA Damage Response (DDR) is a system in our cells that helps protect the DNA from damage. 

It includes various repair methods, processes that help the cell cope with damage, and checkpoints that control the cell cycle. These mechanisms work together to fix damage to the DNA, keeping the genetic information stable. 

The DDR is essential for protecting cells from damage caused by environmental factors, replication errors, and oxidative stress. If these processes are disrupted, genomic instability can result, contributing to diseases such as cancer and neurodegenerative disorders.

It is tightly regulated, and specific pathways are activated depending on the type of DNA damage and the phase of the cell cycle.

What is the ATM?

ATM (ataxia-telangiectasia mutated) is a key kinase protein in the DDR that is primarily activated by double-stranded DNA breaks (DSBs). 

It is an essential upstream protein that initiates DNA repair, cell cycle arrest, and apoptosis by phosphorylating various substrates to maintain genomic stability.

Conditions Associated with BRAT1 Gene Mutations

The following conditions are associated with BRAT1 gene mutations:

Lethal Neonatal Rigidity and Multifocal Seizure Syndrome (RMFSL)

Lethal Neonatal Rigidity and Multifocal Seizure Syndrome (RMFSL) presents with severe developmental delay, intractable seizures, hypertonia, and dysautonomia, leading to early death. Brain imaging typically reveals cerebellar atrophy and significant neuronal loss, underscoring the severity of the condition.

Neurodevelopmental Disorder with Cerebellar Atrophy and Seizures (NEDCAS)

Neurodevelopmental Disorder with Cerebellar Atrophy and Seizures (NEDCAS) is a milder phenotype associated with BRAT1 mutations. Patients with NEDCAS exhibit developmental delay, intellectual disability, ataxia, and seizures. 

While still presenting with significant neurological challenges, individuals with NEDCAS often survive beyond infancy and may show continued developmental progress.

Epileptic Encephalopathy with Migrating Focal Seizures (EIMFS)

Epileptic Encephalopathy with Migrating Focal Seizures (EIMFS) is a severe form of epileptic encephalopathy characterized by seizures that migrate between hemispheres, often starting in early infancy. This condition is marked by refractory seizures that are difficult to control and can lead to significant developmental impairment.

Cerebellar Atrophy with Developmental Delay

In Cerebellar Atrophy with Developmental Delay, cerebellar atrophy is observed alongside varying degrees of developmental delay, intellectual disability, and ataxia. These individuals may show chronic neurological issues but do not experience the rapid progression seen in more severe forms of BRAT1 mutation-related disorders.

These conditions emphasize the broad clinical spectrum associated with BRAT1 mutations, from fatal neonatal disorders to less severe, chronic conditions affecting development and neurological function.

Who Should Get BRAT1 Expression Assessed?

Currently, BRAT1 expression is assessed primarily in research settings. However, there are specific contexts in which assessing BRAT1 may be relevant:

Infants and Children with Serious Neurological Problems

BRAT1 testing should be considered for children with intellectual disability (ID), developmental delays, or ataxia/dyspraxia, particularly if cerebellar atrophy is present on brain imaging. 

It may also be relevant for children with non-progressive cerebellar ataxia or dyspraxia, microcephaly combined with developmental delays and neurological signs, or epilepsy, especially if seizures have a later onset, are difficult to control, or are associated with cerebellar atrophy.

People with A Family History of Neurological Disorders or BRAT1 Mutations

Individuals with a family history of neurological disorders similar to BRAT1-related conditions (e.g., intellectual disability, ataxia, seizures) should consider genetic testing for BRAT1 mutations.

Family members of individuals with BRAT1 mutations–particularly if they exhibit signs of neurodevelopmental disorders like ataxia, intellectual disability, or developmental delays–may also consider this testing, especially if they plan to become pregnant.

Test Procedure and Interpretation

The following section outlines the typical test procedure and interpretation for BRAT1 genetic testing:

Testing Procedure

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for BRAT1 genetic testing are considered to be without mutations that can alter the activity of the BRAT1 proteins.

Clinical Implications of Positive BRAT1 Mutations

The clinical implications of a positive BRAT1 mutation test result will vary by individual, although BRAT1 mutations in symptomatic patients signal an immediate need for further assessment and possibly treatment. 

Patients or practitioners with questions about the clinical implications of BRAT1 mutations should seek further assessment with a genetic counselor or expert. 

Diagnostic Limitations

While BRAT1 testing can provide valuable insights, it is important to interpret results carefully. The presence of BRAT1 mutations should not be used in isolation for diagnosis. 

Clinicians must consider other biomarkers and clinical factors when making decisions about patient care. Additionally, sample handling and patient conditions can impact test results, so ensuring proper testing procedures is essential.

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