Hereditary Sensory Neuropathy, Type IE via the DNMT1 Gene

Hereditary sensory neuropathy type IE (HSN1E, OMIM 614116) was first described in a multi-generational American family with adult-onset distal sensory impairment and subsequent progressive memory and sensorineural hearing loss. Onset of dementia occurred between the second and fourth decades of life and death occurred in the fifth and sixth decades of life (Wright and Dyck, Neurology 45:560-562, 1995). A sibship of affected individuals from Japan has also been reported with early adulthood-onset peripheral sensory neuropathy, followed by hearing loss and progressive dementia (Hojo et al. Europ J Neurol 6:357-361, 1999). Neuropathology studies showed almost complete loss of myelinated nerve fibers and moderate loss of unmyelinated fibers and brain imaging revealed frontal atrophy. In affected individuals from both published families no autonomic or motor symptoms were present. Two other HSN1E families were reported with development of sensorineural deafness and sensory neuropathy between 20 and 35 years of age (Klein et al. Nat Genet 43:595-600, 2011). Brain imaging showed cerebral atrophy and other studies were consistent with a length-dependent progressive sensory axonal loss. Sensory loss often leads to painless trauma and ulcerations of the extremities and subsequent amputations of distal extremities in approximately half of patients (Klein. GeneReviews 2012).

Hereditary sensory neuropathy type IE is inherited as an autosomal dominant disorder. To date only two variants of the DNMT1 gene (OMIM 126375) have been reported in four unrelated families (Klein et al. Nat Genet 42:595- 600, 2011). Three American families and one Japanese family were found to have a c.1532A>G (p.Tyr511Cys) variant and two European families were found to have a c.1518_1520delTCCinsATA (p.Asp506_Pro507delinsGluTyr) variant. Both variants are located within the targeting-sequence domain of DNMT1 (amino acids p.Pro306_Ile620, exons 12-22).

Too few cases of HSN1E have been reported to estimate clinical and analytical sensitivity.

This test provides full coverage of all coding exons of the DNMT1 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).