A novel SCN9A splicing mutation in a compound heterozygous girl with congenital insensitivity to pain, hyposmia and hypogeusia

Margherita Marchi; Vincenzo Provitera; Maria Nolano; Marcello Romano; Simona Maccora; Ilaria D'Amato; Erika Salvi; Monique Gerrits; Lucio Santoro; Giuseppe Lauria

doi:10.1111/jns.12280

journal article Open Access Jul 23, 2018

A novel SCN9A splicing mutation in a compound heterozygous girl with congenital insensitivity to pain, hyposmia and hypogeusia

Margherita Marchi

Vincenzo Provitera

Maria Nolano

Marcello Romano

Simona Maccora Ilaria D'Amato Erika Salvi

Monique Gerrits Lucio Santoro Giuseppe Lauria

Journal of the Peripheral Nervous System Vol. 23 No. 3 pp. 202-206 · Wiley

View at Publisher Save 10.1111/jns.12280

Abstract

Congenital insensitivity to pain (CIP) is a rare autosomal recessive disorder presenting with a spectrum of clinical features caused by mutations in different genes. A 10‐year‐old girl with CIP, hyposmia and hypogeusia, and her unaffected twin and parents underwent next generation sequencing of SCN9A exons and flanking splice sites. Transcript analysis from whole blood successfully assayed the effect of the mutation on the mRNA splicing by polymerase chain reaction amplification on cDNA and Sanger sequencing. We identified the novel splicing variant c.1108‐2A>G compound with the p.Arg896Gln (c.2687G>A) missense mutation previously described in a homozygous patient. The new intronic variant was predicted to induce exon 10 skipping. Conversely, SCN9A mRNA assay demonstrated its partial deletion with a loss of 46 nucleotides causing a premature stop codon in position p.Gln369 (NP_002968). Genetic analysis showed that the two variants were biallelic, being the mother and brother heterozygous carriers of the missense mutation, and the father heterozygous for the splicing mutation. Skin biopsy showed lack of Meissner's corpuscles, loss of epidermal nociceptors and normal autonomic organ innervation. We report a novel splicing mutation and provide clues on its pathogenic effect, broadening the spectrum of genotypes and phenotypes associated to CIP.

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References

21

[1]

10.1016/j.tins.2015.08.010

[2]

10.1097/00005053-193206000-00002

[3]

Schon K (1993)

[4]

10.1038/ng0896-485

[5]

10.1002/humu.23123

[6]

An SCN9A channelopathy causes congenital inability to experience pain

James J. Cox, Frank Reimann, Adeline K. Nicholas et al.

Nature 10.1038/nature05413

[7]

10.1111/jns.12123

[8]

10.1002/humu.21325

[9]

Loss‐of‐function mutations in the Na v 1.7 gene underlie congenital indifference to pain in multiple human populations

YP Goldberg, J MacFarlane, ML MacDonald et al.

Clinical Genetics 10.1111/j.1399-0004.2007.00790.x

[10]

10.1159/000314692

[11]

10.1016/j.pain.2009.02.016

[12]

Peddareddygari LR "Congenital insensitivity to pain: a case report and review of the literature" Case Rep Neurol Med (2014)

[13]

10.1016/j.pediatrneurol.2013.09.007

[14]

10.1016/j.ejpain.2010.07.003

[15]

10.12688/f1000research.2642.2

[16]

10.1111/j.1526-4637.2011.01237.x

[17]

10.1093/hmg/ddm160

[18]

10.1212/wnl.0b013e3182904fdd

[19]

10.1111/bjd.13096

[20]

10.1038/ng.2767

[21]

10.1136/jmedgenet-2015-103646

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References

Details

Published: Jul 23, 2018
Vol/Issue: 23(3)
Pages: 202-206
License: View

Authors

M

Margherita Marchi

Neuroalgology Unit IRCCS Foundation “Carlo Besta” Neurological Institute Milan Italy

V

Vincenzo Provitera

Neurology Department Istituti Clinici Scientifici Maugeri, IRCCS Telese Terme Benevento Italy

M

Maria Nolano

Neurology Department Istituti Clinici Scientifici Maugeri, IRCCS Telese Terme Benevento Italy; Department of Neurosciences, Reproductive Sciences and Odontostomatology University Federico II Naples Italy

M

Marcello Romano

Department of Neurology AOOR Villa Sofia Cervello Palermo Italy

S

Simona Maccora

IRCCS “Bonino‐Pulejo” Messina Italy

I

Ilaria D'Amato

Neuroalgology Unit IRCCS Foundation “Carlo Besta” Neurological Institute Milan Italy

E

Erika Salvi

Neuroalgology Unit IRCCS Foundation “Carlo Besta” Neurological Institute Milan Italy; Department of Health Sciences University of Milan Milan Italy

M

Monique Gerrits

Clinical Genetics and Department of Neurology Maastricht University Medical Center Maastricht The Netherlands

L

Lucio Santoro

Department of Neurosciences, Reproductive Sciences and Odontostomatology University Federico II Naples Italy

G

Giuseppe Lauria

Neuroalgology Unit IRCCS Foundation “Carlo Besta” Neurological Institute Milan Italy; Department of Biomedical and Clinical Sciences “Luigi Sacco” University of Milan Milan Italy

Funding

H2020 Marie Skłodowska-Curie Actions Award: 721841

FP7 Health Award: 602273

Cite This Article

Margherita Marchi, Vincenzo Provitera, Maria Nolano, et al. (2018). A novel SCN9A splicing mutation in a compound heterozygous girl with congenital insensitivity to pain, hyposmia and hypogeusia. Journal of the Peripheral Nervous System, 23(3), 202-206. https://doi.org/10.1111/jns.12280

A novel SCN9A splicing mutation in a compound heterozygous girl with congenital insensitivity to pain, hyposmia and hypogeusia

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