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

• Published in: Journal of the neurological sciences 2021-08, Vol.427, p.117498-117498, Article 117498
• Main Authors: Cintra, Vivian Pedigone, Dohrn, Maike F., Tomaselli, Pedro José, Figueiredo, Fernanda Barbosa, Marques, Sandra Elisabete, Camargos, Sarah Teixeira, Barbosa, Luiz Sergio Mageste, P. Rebelo, Adriana, Abreu, Lisa, Danzi, Matt, Marques, Wilson, Züchner, Stephan
• Format: Article
• Language: English
• Subjects: Autonomic disturbances; Brazil; Congenital insensitivity to pain; GTP Phosphohydrolases - genetics; Hereditary Sensory and Autonomic Neuropathies - genetics; Hereditary sensory neuropathy; Heterozygote; Humans; Mutation; Mutation - genetics; NAV1.7 Voltage-Gated Sodium Channel - genetics; Next generation sequencing; Pain Insensitivity, Congenital - genetics; Serine C-Palmitoyltransferase
• ISSN: 0022-510X; 1878-5883
• DOI: 10.1016/j.jns.2021.117498

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. [Display omitted] •Whole genome sequencing in the first cohort of Brazilian patients with HSN.•Enrichment of the genetic variant spectrum of HSN.•Pathogenic variants in ATL3, SPTLC2, and SCN9A.•Novel pathogenic variants in SCN9A.