# Homozygosity for a Rare Plec Variant Suggests a Contributory Role in Congenital Insensitivity to Pain

## TL;DR

A rare genetic variant in the Plec gene is linked to a condition where people cannot feel pain, affecting multiple body systems.

## Contribution

The study identifies a novel Plec variant associated with congenital insensitivity to pain and related developmental anomalies.

## Key findings

- A homozygous p.Arg1347Cys variant in the Plec gene was found in two patients with congenital insensitivity to pain.
- The Plec variant affects the spectrin repeat 9 region, potentially destabilizing the plakin domain.
- Plec appears to play a role in the development of the maxilla, mandible, cornea, and distal phalanges.

## Abstract

Congenital insensitivity to pain is a rare human condition in which affected individuals do not experience pain throughout their lives. This study aimed to identify the molecular etiology of congenital insensitivity to pain in two Thai patients. Clinical, radiographic, histopathologic, immunohistochemical, and molecular studies were performed. Patients were found to have congenital insensitivity to pain, self-mutilation, acro-osteolysis, cornea scars, reduced temperature sensation, tooth agenesis, root maldevelopment, and underdeveloped maxilla and mandible. The skin biopsies revealed fewer axons, decreased vimentin expression, and absent neurofilament expression, indicating lack of dermal nerves. Whole exome and Sanger sequencing identified a rare homozygous variant c.4039C>T; p.Arg1347Cys in the plakin domain of Plec, a cytolinker protein. This p.Arg1347Cys variant is in the spectrin repeat 9 region of the plakin domain, a region not previously found to harbor pathogenic missense variants in other plectinopathies. The substitution with a cysteine is expected to decrease the stability of the spectrin repeat 9 unit of the plakin domain. Whole mount in situ hybridization and an immunohistochemical study suggested that Plec is important for the development of maxilla and mandible, cornea, and distal phalanges. Additionally, the presence of dental anomalies in these patients further supports the potential involvement of Plec in tooth development. This is the first report showing the association between the Plec variant and congenital insensitivity to pain in humans.