Hereditary Sensory and Autonomic Neuropathy Panel

Hereditary sensory and autonomic neuropathy (HSAN) is a heterogeneous group of slowly-progressing neurological diseases characterized by progressive dysfunction of peripheral sensory nerves. The main feature of this disorder is the loss of large myelinated and unmyelinated nerve fibers (Auer-Grumbach, 2013. PubMed ID: 23931820; Kurth, 2015. PubMed ID: 26219509; Mroczek et al., 2015. PubMed ID: 26232991). Based on clinical features, age at onset, mode of inheritance and causative genes, HSAN can be subdivided into seven distinct types, HSAN1-7 (Rotthier et al., 2012. PubMed ID: 22270030; UpToDate). There are a few cases that do not fit well into this classification.

HSAN1 is the most common type of HSAN, and its main clinical features are loss of pain and temperature sensation with adolescence or adult onset. HSAN1 manifests progressive degeneration of dorsal root ganglion (DRG), leading to distal sensory loss (Houlden et al., 2006. PubMed ID: 16364956). Some patients also have variable defects of autonomic and motor systems (Rotthier et al., 2012. PubMed ID: 22270030). The symptoms of HSAN2 can be similar to that in HSAN1, but HSAN2 usually develops in infancy or early childhood (Indo, 2014. PubMed ID: 20301726).

HSAN3, also known as familial dysautonomia or Riley-Day syndrome, occurs almost solely in children of Ashkenazi Jewish decent. This disorder is characterized by episodes of dysautonomic crises, such as nausea and vomiting. These crises are usually triggered by emotional and physical stress (Shohat et al., 1993. PubMed ID: 20301359).

HSAN4 is also called congenital insensitivity to pain with anhidrosis (CIPA). Sense of touch and vibration are usually normal. Intellectual disability and episodic hyperthermia are also observed in some affected individuals. HSAN5 has marked clinical overlap with HSAN4, however, in HSAN5 patients anhidrosis is less obvious (Indo, 2014. PubMed ID: 20301726).

HSAN6 is characterized by muscle weakness, feeding and respiratory difficulties, and delay in psychomotor development. Autonomic dysfunctions in some patients include lack of corneal reflexes and labile cardiovascular function (Edvardson et al., 2012. PubMed ID: 22522446).

HSAN7 is characterized by congenital indifference to pain. Muscular weakness, gastrointestinal dysfunction, hyperhidrosis and intolerance to moderate heat have also been found in affected patients (Leipold et al. 2013; Woods et al. 2015).

Due to the clinically and genetically heterogeneous features and lack of simple diagnostic measures, HSAN is frequently misdiagnosed. Molecular genetic testing is particular useful to reach an accurate diagnosis.

Hereditary sensory and autonomic neuropathy can be inherited in an autosomal dominant (AD) or autosomal recessive (AR) manner. The ATL1, ATL3, DNMT1, RAB7A, SCN11A, STPLC1 and SPTLC2 genes are related to AD HASN. AR forms of HSAN involve the CCT5, CLTCL1, DST, RETREG1/FAM134B, FLVCR1, ELP1/IKBKAP, KIF1A, NGF, NTRK1, POLG, PRDM12, SCN9A and WNK1 genes. See individual gene test descriptions for information on molecular biology of gene products.

It is difficult to estimate the clinical sensitivity of this test due to the lack of large cohort studies. This panel analyzes 20 genes, including the most common genetic causes of Hereditary Sensory and Autonomic Neuropathy (HSAN). To increase the clinical sensitivity, the genes identified most recently are also included.

Clinical sensitivity of this test is expected to be low because relatively few gross deletions/insertions/duplications have been reported in these genes (Human Gene Mutation Database).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.6% coverage of all coding exons of the genes 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 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).