Hereditary Sensory Neuropathy Type IA via the SPTLC1 Gene

Hereditary Sensory Neuropathy Type IA (HSN1A) is an axonal form of Charcot-Marie-Tooth neuropathy (hereditary motor and sensory neuropathy) (Nicholson et al. 2015. PubMed ID: 20301563). Patients with this disorder manifest prominent sensory loss, “burning” and “shooting” pains (Rotthier et al. 2011. PubMed ID: 21618344). The loss of sensation may lead to painless injuries, which, if unheeded, could result in osteomyelitis and require distal amputations (Rotthier et al. 2009. PubMed ID: 19651702; Auer-Grumbach et al. 2013. PubMed ID: 23454272; Nicholson et al. 2015. PubMed ID: 20301563). Motor involvement is usually observed in advanced cases and patients may become wheelchair-bound in their 60s or 70s (Auer-Grumbach et al. 2013. PubMed ID: 23454272). The disease onset is highly variable (Nicholson et al. 2015. PubMed ID: 20301563).

HSN1A is inherited in an autosomal dominant (AD) manner, and incomplete penetrance has been reported (Houlden et al. 2006. PubMed ID: 16364956; Nicholson et al. 2015. PubMed ID: 20301563). This disorder is caused by pathogenic variants in the SPTLC1 (serine palmitoyltransferase, long chain base subunit 1) gene, which encodes an enzyme involved in sphingolipid biosynthesis (Bejaoui et al. 2001. PubMed ID: 11242106; Dawkins et al. 2001. PubMed ID: 11242114). To date, only missense variant in this gene has been reported to cause disease (Human Gene Mutation Database). Pathogenic variants in the active sites of SPTLC1 lead to a gain-of-function by altering substrate specificity and producing toxic sphingolipids. The accumulation of neurotoxic lipids 1-deoxy-sphinganine and 1-deoxymethyl-sphinganine has been observed in the plasma of patients with HSN1A (Penno et al. 2010. PubMed ID: 20097765).

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 SPTLC1 gene reported to date can be detected by sequencing.

This test provides full coverage of all coding exons of the SPTLC1 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).