Cause and underlying mechanism
EBF3-related HADD syndrome is caused by either a deletion at chromosome 10q26 that includes the EBF3 gene or mutations in EBF3 that are scattered throughout the gene (NM_001005463.2) in one copy of the gene. The majority of the EBF3 mutations identified to date affect the ability of EBF3 to bind to DNA. The loss of EBF3’s ability to interact with the DNA target results in abnormal activation of gene expression critical for appropriate developmental processes in the brain and other body systems.
In order to study the networks of nerve cells and the activity of different genes researchers have developed fruit fly and mouse models of EBF3-related HADDS. Using these disease models allows us to perform a lot of fundamental research. This research is integrated from the clinical findings obtained through our longitudinal natural history study.
Genetic testing
We all have two copies of the EBF3 gene. Individuals with HADDS have one functional copy and the other copy of the EBF3 gene does not work due to a complete loss of that copy or small changes at the nucleotide level.
Genetic testing to detect changes in the EBF3 gene include chromosomal microarray, exome sequencing, or selected gene panels. Microarrays test all chromosomes for changes in copy number. The technique can find pieces of DNA that are missing and pieces that are duplicated. For identification of small changes in the nucleotides, Sanger sequencing of the EBF3 gene is used or even whole exome or genome sequencing.
Testing of family members
The parents of a child with an EBF3 mutation or deletion always have to be tested. Not every change in the nucleotides at the gene level disturbs function of the gene. Testing of the parents by sequencing the EBF3 gene is essential for clinical interpretation of the result. If a mutation is also found in one of the parents, then a clinical assessment of the parent’s birth, development, and childhood history is warranted to evaluate if the parent also has HADDS. If the parent’s history is unrevealing, then the diagnosis of HADDS should be questions when the EBF3 mutation is inherited from a parent.
In case of a deletion or EBF3 mutation that is not found in one of the parents, then the brothers or sisters without any signs of HADDS should not be tested. For them there is not an increased change of having a child with HADDS.