Congenital Insensitivity to Pain with Anhidrosis via the NTRK1 Gene

Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV (HSAN IV), is characterized by insensitivity to pain and inability to sweat (anhidrosis) (Indo 2008., PubMed ID: 20301726). Sweating plays important roles in maintaining normal body temperature, so anhidrosis usually leads to recurrent febrile episodes, which are often the initial manifestations of this disorder (Swanson 1963., PubMed ID: 13979626). The impaired pain sensation may not be apparent in infancy and does not draw attention to parents; therefore it usually results in repeated injuries such as oral self-mutilation, skin infection and multiple bone fractures. In general, the patients’ sensation of touch and vibration are normal (Amano et al., 1998. PubMed ID: 9798226; Kim et al. 2013., PubMed ID: 24070693).

Most patients with CIPA have some degrees of intellectual disability, including impaired conceptual thinking and abstract reasoning. Some children with CIPA also show severe attention-deficit-hyperactivity disorder (ADHD) (Levy-Erez et al., 2010. PubMed ID: 20089052).

CIPA is inherited in an autosomal recessive (AR) manner and is caused by biallelic pathogenic variants in the NTRK1 gene. NTRK1 encodes the neurotrophic tyrosine kinase-1 receptor, which plays important roles in the development of both central and peripheral nervous system (Indo 2008. PubMed ID: 20301726). To date, different types of pathogenic variants (missense, nonsense, splicing variants and frameshift deletions) have been found in the NTRK1 gene (Human Gene Mutation Database). Only one large deletion has been documented (Huehne et al., 2008. PubMed ID: 18077166). Relatively common founder variants have been reported (Indo., 2001. PubMed ID: 11748840). For example, the variant c.1642del (p.Arg548Glyfs*104) accounts for more than 50% of CIPA cases in the Japanese population (Miura et al., 2000. PubMed ID: 10982191). The variant c.1842_1843insT (p.Pro615Serfs*12) has been found in about 89% of pathogenic NTRK1 alleles in Israeli Bedouins (Shatzky et al., 2000. PubMed ID: 10861667). A founder pathogenic variant (c.1615-1G>T) has also been identified in the Turkish population (Tüysüz et al., 2008. PubMed ID: 18322713).

In rare circumstances, a CIPA patient may inherit two defective copies of the NTRK1 gene from one parent, i.e., uniparental disomy (UPD). This type of non-Mendelian inheritance is rare, however, two cases of paternal UPD has been reported in patients with CIPA (Miura et al., 2000. PubMed ID: 11071380; Indo et al., 2001. PubMed ID: 11668614).

Pathogenic variants in the NTRK1 gene account for all cases of CIPA. The clinical sensitivity of this test is expected to be very high (>99%), because it can detect all the documented pathogenic variants in this gene except for a multiexon deletion (Huehne et al., 2008. PubMed ID: 18077166; Human Gene Mutation Database).

This test provides full coverage of all coding exons of the NTRK1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.