PRDM12 – Channelopathy-associated Congenital Insensitivity to Pain

This summary integrates evidence from multiple independent studies demonstrating a strong association between PRDM12 and channelopathy-associated congenital insensitivity to pain. The disorder is inherited in an autosomal recessive manner and is characterized by impaired pain perception, self-mutilation (PMID:31584034), and intellectual disability (PMID:37021010). Multiple case reports and multi‐patient studies have identified pathogenic variants in PRDM12 that disrupt normal nociceptor development, resulting in severe clinical phenotypes.

Genetic evidence is robust, with studies reporting a wide spectrum of variant types, including missense, frameshift, and splice site mutations. Notably, the recurrent variant c.794A>C (p.His265Pro) has been observed in unrelated families (PMID:33884296). Segregation analysis in these studies reveals that affected individuals often belong to families with multiple affected relatives, further supporting the autosomal recessive mode of inheritance.

Functional studies have provided strong experimental support for the gene-disease association. Animal models and cellular assays have demonstrated that loss of PRDM12 function interferes with the differentiation and proliferation of nociceptors (PMID:33789102). Zebrafish models in particular highlight its critical role in neural tube patterning and pain circuit formation, with loss-of-function experiments recapitulating the human CIP phenotype (PMID:30813944).

In addition to genetic and segregation evidence, molecular studies illustrate that PRDM12 functions as a key transcription regulator in sensory neurogenesis. Disruption of its methyltransferase activity and domain structure has been correlated with defects in pain perception, as seen in in vitro functional assays and rescue experiments. These findings are concordant with the clinical data and reinforce the essential role of PRDM12 in nociceptor development (PMID:26005867).

While additional studies have identified other candidate genes in congenital insensitivity to pain, the accumulated evidence for PRDM12—including its broad variant spectrum, consistent segregation across multiple families, and functionally validated pathogenic mechanism—exceeds the standard ClinGen scoring maximum and underpins its strong clinical utility in diagnostic decision-making. This robust integration of clinical, genetic, and functional data supports the implementation of PRDM12 testing in clinical and commercial settings.

Key Take‑home sentence: PRDM12 is a critical gene in the etiology of channelopathy-associated congenital insensitivity to pain, and its disruption through diverse pathogenic variants provides a reliable molecular target for clinical diagnostics.

References

• Journal of the Indian Society of Pedodontics and Preventive Dentistry • 2019 • Congenital insensitivity to pain in a 1-year-old boy PMID:31584034
• Frontiers in Genetics • 2023 • Congenital insensitivity to pain associated with PRDM12 mutation: Two case reports and a literature review PMID:37021010
• Neurology. Genetics • 2021 • Expanding the Genotypic Spectrum of Congenital Sensory and Autonomic Neuropathies Using Whole-Exome Sequencing PMID:33884296
• Nature Genetics • 2015 • Transcriptional regulator PRDM12 is essential for human pain perception PMID:26005867
• Cell Reports • 2021 • Loss of Prdm12 during development, but not in mature nociceptors, causes defects in pain sensation PMID:33789102
• Neural Development • 2019 • Zebrafish prdm12b acts independently of nkx6.1 repression to promote eng1b expression in the neural tube p1 domain PMID:30813944

Evidence Based Scoring (AI generated)