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Gene-disease assertions not curated here (add link or write note):

Disease

congenital insensitivity to pain-hypohidrosis syndrome

Inheritance

Autosomal recessive

Prevalence

 <1 / 1 000 000

Source: ORPHA:478664

Rapid or full curation?

  • Rapid
  • Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

Clinical Validity Scoring Notes and points

  • 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 Validity Points Total

12 POINTS

Source: 26005867, 37021010

Clinical Validity Classification

 Classifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

DEFINITIVE

Source: 26005867, 37021010

Molecular Mechanism

 Mechanisms

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

 options

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

Source:

Age of Onset

 options

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

Congenital

Severity

 Options

Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete.
Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high.
Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced.
Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low.
None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.

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

  • Self mutilating (fingers, oral cavity)

  • cuts and bruises

  • burns

  • recurrent otitis

  • bony deformities

  • corneal injuries

  • anhidrosis

  • Staph aureus infections

  • Typically normal intellect

Sources: PMID: 26005867 29419974

HPO Terms

https://hpo.jax.org/app/

Gene SOPs & Notes

Curation Summary

 Examples

- The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Variable expression or severity:
The severity and expressivity of the disorder is highly variable, even within families.
- If multiple conditions associated with the gene:
It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited

The PRDM12 variant is associated with autosomal recessive hereditary sensory and autonomic neuropathy, also known as congenital insensitivity to pain. It is characterized by an inability to feel pain and 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).

Case ID, Curator name, Date, Jira ticket link

Andrea Oza D-150409532-BH-4037-P-A 01.11.24

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