PMID: 26005867 (2015)- see supplement for pedigrees/variants. Per main text the phenotype of the affected individuals was consistent. Unable to feel acute/inflammatory pain since birth, could not identify noxious heat/cold. Corneal reflexes were absent, which led to progressive corneal scarring. In severely affected individuals, recurrent infections of the skin and occasionally of bones and joints had led to bone deformities and neuropathic joints later in life. Notably, large-fiber sensory modalities (light touch, vibration and proprioception) were mostly normal. Sweating/tearing occurred but less than unaffected relatives. Nerve biopsies showed a severe loss of Aδ fibers in the sural nerves of two patients
c.1056_1076dup p.Ala353_Ala359dup - gAD v4, grpmax of 0.01% 5/15746 Admixed Amer. chr, rare enough for an AR disease. Segregates in 4 affected relatives (consanguineous); however, for only two of the segregations are parents confirmed het only. downgrading for consanguinity, but adding 0.5 points for decreased expression (fig 4)
c.305T>A p.Ile102Asn absent gnomAD, REVEL 0.911- HOM in family B (Italy) 0.5 for the variant, decreased expression (fig 4) +0.5 = 1 POINT
c.91G>T p.Asp31Tyr - absent gnomAD, REVEL Score: 0.553. HOM in family C (Serbia), one unaffected seg. 0.5 for the variant, decreased expression (fig 4) +0.5 = 1 POINT
c.516G>C p.Glu172Asp - absent gAD, REVEL 0.623 in family D (Turkey), one unaffected seg. Downgrading due to consanguinity, but adding points for Decreased expression (fig 4) 0.5 POINTS
c.172dup p.Ser58Lysfs*85 - NMD+, absent gnomAD in family E (Saudi Arabia) 2 POINTS
c.502C>T p.Arg168Cys - grpmax 0.000005530 2/60004 Admixed American, REVEL 0.362 in family F. Downgrading due to consanguinity, no points (Colombia)
c.866A>T p.His289Leu - absent gAD, REVEL Score: 0.958 in family G (Turkey), one unaffected seg. Downgrading due to consanguinity, but adding points for Decreased expression (fig 4) 0.5 POINTS
c.502C>T p.Arg168Cys - grpmax 0.000005530 2/60004 Admixed American, REVEL 0.362 in family H (Afghanistan) with one segregation. Downgrading due to consanguinity but adding points for decreased expression (fig 4) 0.5 POINTS
c.480G>C p.Trp160Cys - absent gnomAD in family I (Turkey), monozygotic twins, one unaffected seg. Downgrading due to consanguinity but adding points for decreased expression (fig 4) 0.5 POINTS
c.1059_1076dup p.Ala354_Ala359dup - absent gnomAD, but there are a lot of del/dups in this region. in family J (Ireland), 3 affected segs, two unaffected. Decreased relative expression fig 4a (0.5 points)
c.683-1G>A - absent gnomAD, last exon acceptor site, NMD- in family K (Sri Lanka). Downgrading due to consanguinity 1-0.5 = 0.5 POINTS
TOTAL SEGS: 6 AFFECTED, 6 UNAFFECTED - 2 POINTS SEG
EXPERIMENTAL
In mice, expressed in sensory spinal ganglia. In human induced pluripotent stem cells, expressed in nociceptor-like nuerons. Knockdown in Xenopus showed irregular distribution of marker genes of cranial sensory placodes. EXPRESSION 1 POINT
PMID: 37021010 (2023)
Case 1: compound het for c.682+1G>A (1 allele gnomAD, last exon donor site, NMD-) and c.502C>T(p.R168C) described above. 1 point + 0.5 point = 1.5 point
Case 2 - no variants described
Source:
Clinical ValidityPoints Total
12 POINTS
Source: 26005867, 37021010
Clinical ValidityClassification
Definitive (12pts)
Strong (12pts)
Moderate (7-11pts)
Limited (0.1-6pts)
No genetic evidence
Refuted
Disputed
DEFINITIVE
Source: 26005867, 37021010
MolecularMechanism
Loss of function
Gain of function
Dominant negative
Unknown
Other
Likely loss of function - depending on view of the animal models could be upgraded to LOF. But the variant I am curating is not LOF so I am stopping the curation here
c.172dup p.Ser58Lysfs*85 - NMD+, absent gnomAD in family E (Saudi Arabia)
c.224-2A>G (NMD+) PMID: 28050684 - Homozygous in patient with ereditary sensory polyneuropathy, pain insensitivity
Mouse/Animal studies
PMID: 34961757- conditional knockout model in mouse. responses to thermal and mechanical nociceptive stimuli but a reduced response to capsaicin and hypersensitivity to formalin-induced inflammatory pain. In mice, constitutive deletion of Prdm12 or its conditional deletion during neurogenesis (from E13.5, in differentiating post-mitotic cells) results in the selective loss of the entire nociceptive lineage
PMID: 30917305 - in mouse, inactivation of the transcriptional regulator PRDM12, which is essential for pain perception in humans, results in a complete absence of the nociceptive lineage, while proprioceptive and touch-sensitive neurons remain.
Penetrance
Complete (100%)
High (≥80%)
Moderate (<80% and >20%)
Low (≤20%)
(list source/PMID)
Source:
Age of Onset
Congenital
Pediatric
Adolescent
Adulthood
Late adulthood
(list source/PMID)
Congenital
Severity
Clinical Features
er main text the phenotype of the affected individuals was consistent. Unable to feel acute/inflammatory pain since birth, could not identify noxious heat/cold. Corneal reflexes were absent, which led to progressive corneal scarring. In severely affected individuals, recurrent infections of the skin and occasionally of bones and joints had led to bone deformities and neuropathic joints later in life. Notably, large-fiber sensory modalities (light touch, vibration and proprioception) were mostly normal. Sweating/tearing occurred but less than unaffected relatives. Nerve biopsies showed a severe loss of Aδ fibers in the sural nerves of two patients
The PRDM12 gene is associated with autosomal recessive congenital insensitivity to pain-hypohidrosis syndrome. It is characterized by an inability to feel pain, absent corneal reflexes, anhidrosis, and staphylococcal infections. Due to inability to feel pain, affected individuals may have self-mutilating injuries (especially to the oral cavity and fingers), cuts and bruises, burns, bony deformities, and corneal injuries (PMID: 26005867 29419974).