New mutations of the gene EBF3 in
patients with a newly described neurodevelopmental syndrome, with features in common with
autism, has been discovered by an international team of scientists.
Identification of these gene variants leads to a better
understanding of these complex conditions and opens the possibility of
diagnosing other previously undiagnosed patients with similar clinical
disorders. The study appears in the American Journal of Human Genetics
‘New mutations of the gene EBF3 leads to developmental delay, coordination problems, limited facial expressions at an early age and abnormal verbal communication and social behaviors.’
"We investigate the genetic causes of complex neurological conditions
of various types, such as autism spectrum disorders and intellectual
disability," said first author Dr. Hsiao-Tuan Chao, postdoctoral
research fellow of pediatric-neurology at Baylor College of Medicine.
"Such conditions are long-lasting, manifest very early in life and range
from mild to severe. They can affect different neurological functions;
however, sometimes they have overlapping similarities. For many of these
conditions there is no definite diagnosis, treatments are limited and
there is no cure."
Chao and colleagues have taken a step toward better understanding some
of these conditions. They discovered new mutations of the gene EBF3 in
three patients presenting with a newly described syndrome.
patients' main features include developmental delay, coordination
problems, limited facial expressions at an early age and abnormal verbal
communication and social behaviors. They can also present with
repetitive motor movements, high threshold to pain and cognitive
impairments," said Chao. "This newly described syndrome has many
similarities with what we see in autism spectrum disorders, but also
The researchers used whole exome sequencing, a laboratory technique
that allows the identification of all the genes in an individual's
genome. In the patients, they identified two new variants of the gene
EBF3 that were not present in the patients' parents. Mutations of EBF3
are rare in the general population but more common in a population of
individuals with autism spectrum disorders and intellectual disability.
"The gene is known to be essential for normal development of the
nervous system," said Chao. "It is one of the key factors involved in
how neurons develop and connect with each other, but has not been
studied in detail. In animal models, mutations that cause the gene to
lose its function result in death of the embryo. EBF3 had never before
been associated with a disease."
Models show gene EBF3 causes neurodevelopmental disorders
That the three patients with developmental disorders have mutations
in the same gene is not sufficient proof that the mutations cause the
condition. To determine whether the mutations can cause
neurodevelopmental problems the scientists tested the effect of the
mutations in the laboratory fruit fly, Drosophila melanogaster.
"We genetically engineered fruit flies to carry the mutations present
in the patients," said Chao. "The defective gene product was not able
to carry on the functions of the normal gene; the effect is so severe
that the fly embryos do not survive. On the other hand, when we
introduced the normal version of the human gene, the files developed
The identification of variants of EBF3 that can cause
neurodevelopmental disorders has improved the genetic diagnosis of these
conditions."We are able to provide a genetic diagnosis for patients who
did not know the cause of their condition," said Chao.
some relief to their parents and the possibility of reaching for support
from a community of parents whose children are affected by similar
disorders. In addition, by gaining a better understanding of how people
are affected by EBF3 dysfunction, we as physicians are better equipped
to prognosticate the developmental outcomes for these children."
able to see our research in fruit flies help us diagnose a patient in
our own hospital was very gratifying. Knowing the genetic basis allows
for more insights into this disorder of the brain," said Dr. Michael F.
Wangler, assistant professor of molecular and human genetics at Baylor, a
senior author on the paper.