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.

中文翻译：

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巴基斯坦家庭对先天性疼痛不敏感的新型双等位基因单碱基插入WNK1中。

遗传性II型感觉神经和自主神经病（HSANII）是一种罕见的，隐性遗传的神经系统疾病，通常涉及对疼痛的不敏感性。HSAN2A亚型是WNK1基因突变产生的。我们确定了一个近亲的巴基斯坦家庭，其中三人受到感染，表现出HSANII症状。我们进行了微阵列基因分型，随后进行了纯合-下降（HBD）作图，这表明了几个重要的HBD区，包括〜6 Mb朝向12p染色体末端，跨越了WNK1。同时，我们对其中一个受影响的兄弟进行了全外显子组测序（WES），并在第10外显子中鉴定了一个纯合的1 bp插入变异Chr12：978101dupA。该变异确认已在家族中分离，预计将截断该蛋白。 （NM_213655.4：c.3464delinsAC; p。（Thr1155Asnfs * 11）并导致无义介导的转录本mRNA衰变。先前在巴基斯坦家庭中对先天性疼痛不敏感/ HSANII的研究已经鉴定出SCN9A中的突变。我们的研究确定了巴基斯坦家庭中先前未报道的WNK1突变与先天性疼痛不敏感/ HSANII分离。