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

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.

Diagnostic criteria for small fibre neuropathy in clinical practice and research

“…However, it does not arise from the lack of knowledge on the diagnostic performance of tests for small nerve fibre functioning or morphometric assay, but rather from how their combination meets the diagnostic requirements for individual patients at the clinical level. Indeed, abnormal findings in some small nerve fibre-related tests, such as skin biopsy, QST or laser-evoked potentials can occur in painful clinical conditions irrespective of the localization, nature and aetiology of pain (Devigili et al , 2008; Backonja et al , 2013; Terkelsen et al , 2017; Uceyler et al , 2018) and even in painless neuropathies or systemic diseases (Nolano et al , 2001, 2008; Bennett and Woods, 2014; Dalla Bella et al , 2016; Marchi et al , 2018). In such a frame, patients’ symptoms and signs of small nerve fibre dysfunction are crucial to the reliable interpretation of the findings obtained by the diagnostic tests.…”

The mechanism of analgesia in NaV1.7 null mutants

“…33 Studies of humans with loss-of-function mutations in NaV1.7 posit die back of peripheral nerves as a significant mechanism of analgesia. 11,34,35 In three human NaV1.7 null individuals, microneurographic recording found evidence for Aδ but not C fibres, based on activity-dependent slowing profiles. 11 These subjects were not challenged with painful stimuli.…”

Novel SCN9A Mutations in a Compound Heterozygous Girl with Congenital Insensitivity to Pain

“…This relatively innocent disease may eventually have seriously life-threatening complications if not recognized in time. 12 The absence of normal pain behavior often results in more serious traumatic complications with increasing age as a result of engaging in more harmful behavior such as excessive risk taking in sports. This can ultimately lead to a reduced life expectancy.…”