Whole exome sequencing to unravel the genetics of neuralgic amyotrophy

Neuralgic amyotrophy (NA) occurs in both idiopathic and hereditary forms (INA
and HNA, respectively), HNA is thought to be 10 times less common than INA. HNA
is an autosomal dominant, monogenic disorder with high but incomplete
penetrance and evidence of genetic heterogeneity. SEPT9 is the only gene known
to be associated with HNA. In our cohort of 944 NA patients, 120 suffer from
HNA and 38 have been screened for the SEPT9 mutation in a pilot study. We
identified copy number changes in 5 families and only one mutation in a patient
with a duplication of the gene (unpublished data). The genetic basis for INA is
even less clear. To date no mutations have been reported that can explain this
form of NA.

Molecular genetic testing for SEPT9 mutations is clinically available, but is
not of much added value, at least in the Netherlands because of the low
prevalence of SEPT9 mutations observed in Dutch HNA patients.
Objective 1: To identify with WES de novo mutations in genes, other than SEPT9,
for INA in a trio analysis.
Objective 2: Assess with WES duplication in SEPT9 for HNA
Objective 3: determine potential candidate gene in affected HNA / INA patients
by WES,

Knowledge about the genetic basis of NA will improve our understanding about
the pathophysiology and possible treatments for this disease.

Our centre serves as a national reference centre for NA. In the past years we
collected clinical data and sampled blood for clinical and scientific purposes.
To this unique material we will apply a relatively novel technique, whole exome
sequencing, to identify new genes associated with the disease. In the meanwhile
we will continue to include and sample blood of affected patients with HNA en
INA. To identify de novo mutations, an analysis of the patient and (un)affected
relatives is necessary, we will also ask permission to sample blood from
affected and unaffected relatives of the INA and HNA patients.

Many blood samples of NA patients in the cohort have already been collected.
Potential participants (NA patients or (un)affected relatives) will be offered
an informed consent to collect blood samples for scientific research in genetic
abnormalities. For this an one-off visit to the hospital is necessary to obtain
the blood sample. Except for a possible small local hematoma due to the blood
sample, there are no other risks.
By applying whole exome sequencing incidental findings may occur, i.e. the
identification of a mutation potentially leading to another disease like cancer
or other late onset diseases.