Epi4K consortium.; Epilepsy Phenome/Genome Project..
Ultra-rare genetic variation in common epilepsies: a case-control sequencing
study. Lancet Neurol. 2017 Feb;16(2):135-143.
Abstract
BACKGROUND:
Despite progress in understanding the genetics of rare
epilepsies, the more common epilepsies have proven less amenable to traditional
gene-discovery analyses. We aimed to assess the contribution of ultra-rare
genetic variation to common epilepsies.
METHODS:
We did a case-control sequencing study with exome sequence
data from unrelated individuals clinically evaluated for one of the two most
common epilepsy syndromes: familial genetic generalised epilepsy, or familial
or sporadic non-acquired focal epilepsy. Individuals of any age were recruited
between Nov 26, 2007, and Aug 2, 2013, through the multicentre Epilepsy
Phenome/Genome Project and Epi4K collaborations, and samples were sequenced at
the Institute for Genomic Medicine (New York, USA) between Feb 6, 2013, and Aug
18, 2015. To identify epilepsy risk signals, we tested all protein-coding genes
for an excess of ultra-rare genetic variation among the cases, compared with
control samples with no known epilepsy or epilepsy comorbidity sequenced
through unrelated studies.
FINDINGS:
We separately compared the sequence data from 640
individuals with familial genetic generalised epilepsy and 525 individuals with
familial non-acquired focal epilepsy to the same group of 3877 controls, and
found significantly higher rates of ultra-rare deleterious variation in genes
established as causative for dominant epilepsy disorders (familial genetic
generalised epilepsy: odd ratio [OR] 2·3, 95% CI 1·7-3·2, p=9·1 × 10-8;
familial non-acquired focal epilepsy 3·6, 2·7-4·9, p=1·1 × 10-17). Comparison
of an additional cohort of 662 individuals with sporadic non-acquired focal
epilepsy to controls did not identify study-wide significant signals. For the
individuals with familial non-acquired focal epilepsy, we found that five known
epilepsy genes ranked as the top five genes enriched for ultra-rare deleterious
variation. After accounting for the control carrier rate, we estimate that
these five genes contribute to the risk of epilepsy in approximately 8% of
individuals with familial non-acquired focal epilepsy. Our analyses showed that
no individual gene was significantly associated with familial genetic
generalised epilepsy; however, known epilepsy genes had lower p values relative
to the rest of the protein-coding genes (p=5·8 × 10-8) that were lower than
expected from a random sampling of genes.
INTERPRETATION:
We identified excess ultra-rare variation in known epilepsy
genes, which establishes a clear connection between the genetics of common and
rare, severe epilepsies, and shows that the variants responsible for epilepsy
risk are exceptionally rare in the general population. Our results suggest that
the emerging paradigm of targeting of treatments to the genetic cause in rare
devastating epilepsies might also extend to a proportion of common epilepsies.
These findings might allow clinicians to broadly explain the cause of these
syndromes to patients, and lay the foundation for possible precision treatments
in the future.
____________________________________________________________________
Several genes previously implicated only in rare, severe
forms of pediatric epilepsy may also contribute to common forms of the
disorder, according to a report published online ahead of print January 13 in
Lancet Neurology. “Our findings raise hopes that the emerging paradigm for the
treatment of rare epilepsies, where therapies are targeted to the precise
genetic cause of disease, may also extend to a proportion of common epilepsy
syndromes,” said study leader David B. Goldstein, PhD, Director of the
Institute for Genomic Medicine and Professor in the Departments of Genetics and
Development and Neurology at Columbia University Medical Center in New York
City.
In recent years, researchers have identified dozens of genes
that, alone or in combination with other factors, cause rare pediatric
epilepsies. These discoveries have led to the use of targeted therapies for
some seizure disorders, such as the ketogenic diet for patients with Dravet
syndrome or GLUT-1 deficiency syndrome. Other therapies such as quinidine, a
medication to treat heart arrhythmias, and memantine, an Alzheimer’s disease
treatment, have been tried in children with certain gene mutations. These
attempts have not proved universally effective for all patients with these
mutations, but suggest the potential to repurpose existing medicines to treat
rare genetic forms of epilepsy…
The researchers separately compared the sequence data from
640 individuals with familial genetic generalized epilepsy and 525 individuals
with familial non-acquired focal epilepsy to the same group of 3,877 controls.
The researchers found significantly higher rates of ultra-rare deleterious
variation in genes established as causative for dominant epilepsy disorders (familial
genetic generalized epilepsy, odd ratio 2.3; familial non-acquired focal
epilepsy, odds ratio 3.6). Comparison of an additional cohort of 662
individuals with sporadic non-acquired focal epilepsy to controls did not
identify study-wide significant signals.
For the individuals with familial non-acquired focal
epilepsy, the researchers found that five known epilepsy genes—DEPDC5, LG11,
PCDH19, SCN1A, and GRIN2A—ranked as the top five genes enriched for ultra-rare
deleterious variation. “After accounting for the control carrier rate, we
estimate that these five genes contribute to the risk of epilepsy in
approximately 8% of individuals with familial non-acquired focal epilepsy,”
said Erin Heinzen Cox, PhD, Assistant Professor in the Department of Pathology
and Cell Biology and Deputy Director of the Institute for Genomic Medicine at
Columbia University Medical Center…
The findings have important implications for clinical
practice and for research. “At present, all common epilepsies are treated the
same way, with the same group of medications,” said Dr. Goldstein. “But as we
identify more of these epilepsy genes that span a much wider range of types of
epilepsy than previously thought, we can begin to try targeted therapies across
these patient populations. As this genetically driven treatment paradigm
becomes more established, our field, which is accustomed to undertaking large
clinical trials in broad patient populations, will need to take a new approach
to clinical research, focusing on patients based on their genetic subtype.”
“This is a very exciting breakthrough in the treatment of
epilepsy, in which current treatment is based on whether a child has focal
seizures or generalized seizures,” said James J. Riviello, MD, the Sergievsky
Family Professor of Neurology and Pediatrics and Chief of Child Neurology at
NewYork-Presbyterian Morgan Stanley Children’s Hospital in New York City.
“Genetic testing for epilepsy may allow us to identify the specific
anticonvulsant medication that potentially works best for an individual
patient. We have already identified children in whom knowing the underlying
genetic basis of the epilepsy has guided our treatment choices.”
http://www.mdedge.com/neurologyreviews/article/130389/epilepsy-seizures/common-epilepsies-share-genetic-overlap-rare-types
No comments:
Post a Comment