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

JOURNAL OF THE NEUROLOGICAL SCIENCES

卷:427

Article

Cintra, Vivian Pedigone^1,2  Dohrn, Maike F.^2,3  Tomaselli, Pedro Jose¹  Figueiredo, Fernanda Barbosa¹  Marques, Sandra Elisabete¹  Camargos, Sarah Teixeira⁴  Mageste Barbosa, Luiz Sergio⁴  Rebelo, Adriana P.²  Abreu, Lisa²  Danzi, Matt²  Marques, Wilson, Jr.¹  Zuchner, Stephan² 

[1] Univ Sao Paulo, Ribeirao Preto Sch Med, Ribeirao Preto, SP, Brazil

[2] Univ Miami, Dr John T Macdonald Fdn Dept Human Genet, John P Hussman Inst Human Genom, Miller Sch Med, Miami, FL USA

[3] Rhein Westfal TH Aachen, Med Fac, Dept Neurol, Aachen, Germany

[4] Univ Fed Minas Gerais, Belo Horizonte, MG, Brazil

关键词: Hereditary sensory neuropathy;    Congenital insensitivity to pain;    Autonomic disturbances;    Next generation sequencing;    Mutation;   

DOI  :  10.1016/j.jns.2021.117498

来源: Elsevier

【 摘 要 】

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.

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