Rare mutations in ATL3, SPTLC2 and SCN9A explaining hereditary sensory neuropathy and congenital insensitivity to pain in a Brazilian cohort

Vivian Pedigone Cintra, Maike F. Dohrn, Pedro José Tomaselli, Fernanda Barbosa Figueiredo, Sandra Elisabete Marques, Sarah Teixeira Camargos, Luiz Sergio Mageste Barbosa, Adriana P. Rebelo, Lisa Abreu, Matt Danzi, Wilson Marques, Stephan Züchner

Research output: Contribution to journalArticlepeer-review

Abstract

Hereditary sensory neuropathies (HSN) are a group of rare neurological disorders with heterogeneous clinical and genetic characteristics. Although at least 17 different genes have already been associated with HSN, the epidemiology of the disorder in Brazil is still unknown. Performing whole genome sequencing (WGS) in 23 unrelated Brazilian families diagnosed with HSN, we detected pathogenic variants in ATL3, SPTLC2, and SCN9A in 12 patients belonging to five unrelated families. Clinical features associated with heterozygous mutations in ATL3 (c.575A > G; p.(Tyr192Cys)) and SPTLC2 (c.529A > G; p.(Asn177Asp)) were sensory deficits, neuropathic pain, and recurrent ulcerations. Presenting as congenital insensitivity to pain, three unrelated probands carried biallelic loss-of-function mutations in SCN9A. The so far undescribed stop mutation c.2106G > A (p.(Trp702Ter)) and the likewise novel splicing variant c.3319-1G > A were found in compound-heterozygosity with, respectively, the known pathogenic variants c.2908G > T (p.Trp970Ter) and c.2690G > A (p.Glu897Ter). In total, we identified pathogenic mutations in 21.7% of our families, which suggests that most of the cases could be explained by yet to be discovered genes or unusual alleles. Our study represents the first mutational screen in a Brazilian HSN cohort, enabling additional insights for genotype-phenotype correlations, reducing misdiagnoses, and providing early treatment considerations.

Original languageEnglish (US)
Article number117498
JournalJournal of the Neurological Sciences
Volume427
DOIs
StatePublished - Aug 15 2021
Externally publishedYes

Keywords

  • Autonomic disturbances
  • Congenital insensitivity to pain
  • Hereditary sensory neuropathy
  • Mutation
  • Next generation sequencing

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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