Hereditary Sensory and Autonomic Neuropathy Type VIII via the PRDM12 Gene

Hereditary sensory and autonomic neuropathy type VIII (HSAN8) is characterized by impaired pain and temperature sensation from birth. Chen et al. (2015) reported 11 families with this disorder. Patients usually show oral and tongue lesions, finger biting, facial scratching, and distal ulceration. Affected patients may also have reduced sweat and tear production. Typically, the HSAN8 patients have normal sensation of touch (fine and deep), pressure, vibration and tickle (Chen et al. 2015. PubMed ID: 26005867; Zhang et al. 2016. PubMed ID: 26975306).

The inheritance pattern of HSAN8 in the families reported by Chen et al. (2015) study was consistent with autosomal recessive transmission. This disorder is caused by pathogenic variants in the PRDM12 gene, which encodes a transcription regulator containing a PRDI-BF1 and RIZ homology (PR) domain, a SET domain, and three C2H2 zinc finger DNA-binding domains (Chen et al. 2015. PubMed ID: 26005867). To date, different types of variants (missense, splicing, and a frameshift duplication) have been found in PRDM12 to cause HSAN8 (Human Gene Mutation Database). The Chen et al. (2015) study also identified a 21 bp trinucleotide CGC expansion in the last exon of the PRDM12 gene that caused reduced PRDM12 expression and HSAN8. Animal studies suggested that PRDM12 loss-of-function impaired sensory neuron development and pain sensitivity (Nagy et al. 2015. PubMed ID: 25891934).

It is difficult to estimate the exact clinical sensitivity of this test due to the lack of large cohort studies. All the pathogenic variants in the PRDM12 gene reported to date can be detected by sequencing.

This test provides full coverage of all coding exons of the PRDM12 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).