Abstract Details

Title Loss of Function, Loss of Pain? Novel Variants in SCN9A to Explain Congenital Insensitivity to Pain in Three Brazilian Cases

Topic General Neurology

Presentation(s) Neuroepidemiology Posters (7:00 AM-5:00 PM)

Poster/Presentation
Number 004

Background Congenital insensitivity to pain is a rare, genetic disorder that is associated with severe mutilation and disability. The gene SCN9A encodes the voltage-gated sodium channel Nav1.7 that is responsible for pain perception. Mutations in this gene are associated to either loss or gain of pain, depending on their impact on sodium channel function.

Objective To evaluate the frequency of mutations in SCN9A.

Design/Methods We performed whole genome sequencing (BGISEQ-500) studies in 23 unrelated Brazilian families with hereditary sensory and autonomic neuropathy.

Results

In a 9-year-old girl, we identified the novel stop mutation p.Trp702Ter in SCN9A, which was in compound-heterozygosity with another, previously described stop variant p.Trp970Ter. Both parents were unaffected carriers of one allele, each. The novel variant has not been identified in healthy individuals (GnomAD), and in-silico predictions are pathogenic. As it might most likely lead to a truncated protein, loss-of-function is most likely the pathomechanism. This matches the phenotype of pain insensitivity.

In an 8-year-old boy, likewise with congenital insensitivity to pain, we found the already described stop mutation p.Trp897Ter in compound heterozygosity with the novel splice variant c.3319-1G>A, both in SCN9A. The latter is absent in healthy controls (GnomAD) and is predicted to disrupt the original acceptor splice site of exon 18, suggesting an underyling loss-of-function mechanism again.

A homozygous stop mutation, p.Trp897Ter, was found in a 21-year-old female patient, daughter of consanguineous parents, with congenital insensitivity to pain together with autonomic dysfunction including hypohidrosis. The variant was previously described in association with a loss-of-function mechanism.

Conclusions By whole genome sequencing, we identified biallelic loss-of-function mutations in SCN9A in three unaffected Brazilian families with congenital insensitivity to pain. We conclude that the novel stop mutation p.Trp702Ter and the novel splice variant c.3319-1G>A are most likely pathogenic.

Authors/Disclosures
PRESENTER	No disclosure on file
Maike Dohrn, MD (Department of Neurology, RWTH Aachen University Hospital)	Dr. Dohrn has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Akcea, Alnylam, Pfizer, Amicus. Dr. Dohrn has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Amicus, Akcea. Dr. Dohrn has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Akcea, Alnylam, Pfizer. The institution of Dr. Dohrn has received research support from Pfizer. Dr. Dohrn has received research support from German Research Foundation.
Pedro J. Tomaselli, MD (Clinical Hospital of Ribeirao Preto - USP)	Dr. Tomaselli has nothing to disclose.
Fernanda B. Figueiredo (University)	Miss Figueiredo has nothing to disclose.
	No disclosure on file
Adriana Rebelo	No disclosure on file
	No disclosure on file
Matt Danzi (University of Miami)	Matt Danzi has nothing to disclose.
Stephan Zuchner, MD, FAAN (University of Miami School of Medicine)	Dr. Zuchner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Applied Therapeutics. The institution of Dr. Zuchner has received research support from Muscular Dystrophy Association. The institution of Dr. Zuchner has received research support from CMT Association. Dr. Zuchner has received intellectual property interests from a discovery or technology relating to health care.
Wilson Marques, Jr., MD (School of Medicine of Ribeirao Preto)	Dr. Marques has nothing to disclose.