Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Brief Communication
  • Published:

A novel biallelic single base insertion in WNK1 in a Pakistani family with congenital insensitivity to pain


Hereditary sensory and autonomic neuropathy type II (HSANII) is a rare, recessively inherited neurological condition frequently involving insensitivity to pain. The subtype, HSAN2A, results from mutations in the gene WNK1. We identified a consanguineous Pakistani family with three affecteds showing symptoms of HSANII. We performed microarray genotyping, followed by homozygosity-by-descent (HBD) mapping, which indicated several significant HBD regions, including ~6 Mb towards the terminus of chromosome 12p, spanning WNK1. Simultaneously, we performed whole exome sequencing (WES) on one of the affected brothers, and identified a homozygous 1 bp insertion variant, Chr12:978101dupA, within exon 10. This variant, confirmed to segregate in the family, is predicted to truncate the protein (NM_213655.4:c.3464delinsAC; p.(Thr1155Asnfs*11) and lead to nonsense-mediated mRNA decay of the transcript. Previous studies of congenital pain insensitivity/HSANII in Pakistani families have identified mutations in SCN9A. Our study identified a previously unreported WNK1 mutation segregating with congenital pain insensitivity/HSANII in a Pakistani family.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1

Data availability

Information on the variant reported here has been submitted to the ClinVar database housed by NCBI: ClinVar accession SCV001134973. The microarray and WES data that support the findings of this study are available from the corresponding author upon reasonable request.


  1. Lafreniere RG, MacDonald ML, Dube MP, MacFarlane J, O’Driscoll M, Brais B, et al. Identification of a novel gene (HSN2) causing hereditary sensory and autonomic neuropathy type II through the study of Canadian genetic isolates. Am J Hum Genet. 2004;74:1064–73.

    Article  CAS  Google Scholar 

  2. Rivière JB, Verlaan DJ, Shekarabi M, Lafrenière RG, Bénard M, Der Kaloustian VM, et al. A mutation in the HSN2 gene causes sensory neuropathy type II in a Lebanese family. Ann Neurol. 2004;56:572–5.

    Article  CAS  Google Scholar 

  3. Roddier K, Thomas T, Marleau G, Gagnon AM, Dicaire MJ, St-Denis A, et al. Two mutations in the HSN2 gene explain the high prevalence of HSAN2 in French Canadians. Neurology. 2005;64:1762–7.

    Article  CAS  Google Scholar 

  4. Cho HJ, Kim BJ, Suh YL, An JY, Ki CS. Novel mutation in the HSN2 gene in a Korean patient with hereditary sensory and autonomic neuropathy type 2. J Hum Genet. 2006;51:905–8.

    Article  Google Scholar 

  5. Coen K, Pareyson D, Auer-Grumbach M, Buyse G, Goemans N, Claeys KG, et al. Novel mutations in the HSN2 gene causing hereditary sensory and autonomic neuropathy type II. Neurology. 2006;66:748–51.

    Article  CAS  Google Scholar 

  6. Shekarabi M, Girard N, Rivière JB, Dion P, Houle M, Toulouse A, et al. Mutations in the nervous system-specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II. J Clin Investig. 2008;118:2496–505.

    PubMed  CAS  Google Scholar 

  7. Murray TJ. Congenital sensory neuropathy. Brain. 1973;96:387–94.

    Article  CAS  Google Scholar 

  8. Ota M, Ellefson RD, Lambert EH, Dyck PJ. Hereditary sensory neuropathy, type II. Clinical, electrophysiologic, histologic, and biochemical studies of a Quebec kinship. Arch Neurol. 1973;29:23–7.

    Article  CAS  Google Scholar 

  9. Seelow D, Schuelke M, Hildebrandt F, Nürnberg P. HomozygosityMapper–an interactive approach to homozygosity mapping. Nucleic Acids Res. 2009;37:W593–9.

    Article  CAS  Google Scholar 

  10. Harripaul R, Vasli N, Mikhailov A, Rafiq MA, Mittal K, Windpassinger C, et al. Mapping autosomal recessive intellectual disability: combined microarray and exome sequencing identifies 26 novel candidate genes in 192 consanguineous families. Mol Psychiatry. 2018;23:973–84.

    Article  CAS  Google Scholar 

  11. Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature. 2006;444:894–8.

    Article  CAS  Google Scholar 

  12. Sawal HA, Harripaul R, Mikhailov A, Dad R, Ayub M, Jawad Hassan M, et al. Biallelic truncating SCN9A mutation identified in four families with congenital insensitivity to pain from Pakistan. Clin Genet. 2016;90:563–5.

    Article  CAS  Google Scholar 

  13. Vidal-Petiot E, Cheval L, Faugeroux J, Malard T, Doucet A, Jeunemaitre X, et al. A new methodology for quantification of alternatively spliced exons reveals a highly tissue-specific expression pattern of WNK1 isoforms. PLoS ONE. 2012;7:e37751.

    Article  CAS  Google Scholar 

Download references


The authors thank the family for their participation in this study. This study was supported by funding from the Canadian Institutes of Health Research to JBV (#PJT-156402).

Author information

Authors and Affiliations


Corresponding author

Correspondence to John B. Vincent.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pastore, S., Harripaul, R., Azam, M. et al. A novel biallelic single base insertion in WNK1 in a Pakistani family with congenital insensitivity to pain. J Hum Genet 65, 493–496 (2020).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


Quick links