Abstract
OBJECTIVES: Congenital insensitivity to pain (CIP) is a rare sensory neuropathy marked by absent nociception that predisposes patients to injuries and complications. Variants in genes, particularly PRDM12, underlie the condition. We investigated the molecular basis of CIP in 2 unrelated families. METHODS: Trio whole-exome sequencing was performed for 3 CIP patients from 2 unrelated families and their parents; 1 family with negative results subsequently underwent whole genome sequencing. Sanger sequencing and fluorescent PCR confirmed and sized a GCC repeat expansion. RESULTS: PRDM12 variants explained CIP in both families, each manifesting infantile-onset neuropathic keratopathy and self-mutilation. In Family 1, 2 siblings born to consanguineous parents were homozygous for a 19-GCC repeat expansion in the last exon, resulting in a polyalanine tract of 20 alanines-the largest PRDM12 polyalanine expansion reported to date. In Family 2, the proband carried 2 compound-heterozygous variants c.570+2T > G and c.796A > C (p.Thr266Pro) classified as pathogenic and likely pathogenic, respectively, and both previously undescribed. DISCUSSION: These data broaden the genetic spectrum of CIP and reinforce PRDM12 as a key gene in pain perception. They also emphasize that diagnostic analysis should target both single-nucleotide variants and polyalanine expansions, which are often underrepresented in whole-exome or whole-genome sequencing data.