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Hereditary sensory and autonomic neuropathy (HSAN; MONDO:0015364) comprises a group of rare disorders characterized by sensory axonal degeneration, insensitivity to pain, self-mutilation, recurrent ulcers and autonomic dysfunction. PRDM12 (HGNC:13997) encodes a conserved PR/SET-domain transcription factor critical for nociceptor development and maintenance.
Next-generation sequencing of six unrelated children with HSAN over a 7-year period identified biallelic PRDM12 variants in two probands, alongside causal alleles in NTRK1, DST and FLVCR1 (PMID:35263888). The PRDM12‐positive patients presented with global developmental delay, rhinitis and recurrent corneal erosions mapping to HP:0001263, HP:0012384 and HP:0000495. Inheritance was autosomal recessive, with affected individuals harboring missense and loss-of-function alleles. No founder variants were observed.
Detailed variant analysis from patient fibroblasts and evolutionary modeling identified four disease-causing PRDM12 alleles in HSAN: c.91G>T (p.Asp31Tyr), c.303del (p.Ile102fs), c.503G>A (p.Arg168His) and c.516G>C (p.Glu172Asp) (PMID:25891934). These include two missense substitutions and one frameshift predicted to truncate the PR homology domain, consistent with loss-of-function.
Segregation data are limited by small family sizes, but both probands were homozygous or compound heterozygous for PRDM12 variants, with parents as obligate carriers. Additional affected relatives were not reported.
Functional studies in Xenopus and Drosophila demonstrated that wild-type human PRDM12 induces sensory neuronal marker expression, whereas all four patient variants significantly reduced eng1b expression in the p1 domain, phenocopying HSAN sensory deficits in vivo (PMID:25891934). These models support a loss-of-function mechanism via impaired transcriptional activation of nociceptor fate genes.
Together, genetic and experimental data establish a moderate ClinGen clinical validity for PRDM12 in autosomal recessive HSAN. PRDM12 testing should be included in diagnostic panels for HSAN, with functional assays available for variant interpretation.
Key Take-home: Biallelic PRDM12 loss-of-function variants cause autosomal recessive HSAN by disrupting sensory neuron specification, enabling targeted genetic diagnosis and counseling.
Gene–Disease AssociationModerateBiallelic PRDM12 variants identified in two unrelated HSAN probands with consistent clinical features and supportive functional data Genetic EvidenceLimitedIdentification of biallelic PRDM12 variants in two probands; autosomal recessive inheritance with missense and frameshift alleles Functional EvidenceModerateXenopus and Drosophila models show loss-of-function of patient variants impairing sensory neuron marker induction |