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  • Test code: 03230
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit
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  1. Test Catalog
  2. Invitae Hereditary Sensory and Autonomic Neuropathy Panel

Invitae Hereditary Sensory and Autonomic Neuropathy Panel

Test description

The Invitae Hereditary Sensory and Autonomic Neuropathy Panel analyzes up to 17 genes associated with hereditary sensory and autonomic neuropathy (HSAN), a clinically and genetically heterogeneous group of peripheral nervous system disorders characterized by sensory and autonomic dysfunction. When sensory neurons are predominantly affected without significant autonomic involvement the disorder may also be referred to as hereditary sensory neuropathy (HSN). These genes were curated based on current available evidence to provide a comprehensive test for the genetic causes of HSAN.

Given that hereditary sensory and autonomic neuropathies are a heterogeneous group of disorders, identification of the underlying genetic cause can help predict outcome for the individual, and inform recurrence risk.

Genes tested

Primary panel

ATL1 ATL3 DNMT1 DST ELP1 KIF1A NGF NTRK1 RAB7A RETREG1 SCN11A SCN9A SPTLC1 SPTLC2 WNK1

Add-on Preliminary-evidence Genes for Hereditary Sensory and Autonomic Neuropathy

CCT5 PRDM12

Preliminary-evidence genes currently have early evidence of a clinical association with the specific disease covered by this test. Some clinicians may wish to include genes which do not currently have a definitive clinical association, but which may prove to be clinically significant in the future. These genes can be added at no additional charge. Visit our Preliminary-evidence genes page to learn more.

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Primary panel (15 genes)

ATL1 ATL3 DNMT1 DST ELP1 KIF1A NGF NTRK1 RAB7A RETREG1 SCN11A SCN9A SPTLC1 SPTLC2 WNK1

Panel details and technical assay limitations
Add-on Preliminary-evidence Genes for Hereditary Sensory and Autonomic Neuropathy (2 genes)

Preliminary-evidence genes currently have early evidence of a clinical association with the specific disease covered by this test. Some clinicians may wish to include genes which do not currently have a definitive clinical association, but which may prove to be clinically significant in the future. These genes can be added at no additional charge. Visit our Preliminary-evidence genes page to learn more.

CCT5 PRDM12

Panel details and technical assay limitations

Alternative tests to consider

For a broader analysis of the genetics of hereditary neuropathies:

Clinical information

Hereditary sensory and autonomic neuropathies (HSAN) are a clinically heterogeneous group of disorders that predominantly affect the sensory neurons of the peripheral nervous system, with or without autonomic neuron involvement. Loss of sensory neuron function can lead to complications including frequent injuries, ulcerations, bone infections and amputation. Possible autonomic features include anhidrosis, hyperhidrosis, abnormal blood pressure fluctuations, and gastrointestinal issues. Sensory abnormalities are often more significant than autonomic abnormalities. Motor neuron involvement may also occur in some individuals. Depending on the causative gene, other findings may also be present, such as hearing loss, gait impairment, decreased tendon reflexes, hypotonia, delayed development, and congenital insensitivity to pain. Age of onset varies from infancy to adulthood.

GeneHSAN/HSN subtype or related disorderInheritanceProportion of HSAN CasesTypical age of onset
Autosomal dominantAutosomal recessive
ATL1 HSN1D ✓ unknown early adulthood
ATL3 HSN1F ✓ unknown adolescence to early adulthood
CCT5* HSN with spastic paraplegia ✓ unknown childhood
DNMT1 HSN1E ✓ rare adolescence to early adulthood
DST HSAN6 ✓ rare infancy
ELP1 (formerly known as IKBKAP) Familial dysautonomia (HSAN3) ✓ in Ashkenazi Jews, one mutation accounts for >99% of cases infancy
KIF1A HSN2C ✓ rare childhood
NGF HSAN5 ✓ ✓ 2% infancy
NTRK1 HSAN4 ✓ 6% infancy to childhood
PRDM12* HSAN8 ✓ unknown childhood
RAB7A CMT2B ✓ <1% adolescence to early adulthood
RETREG1 (formerly known as FAM134B) HSAN2B ✓ 2% childhood
SCN11A HSAN7 ✓ unknown infancy
SCN9A HSAN2D ✓ unknown infancy to childhood
SPTLC1 HSAN1A ✓ 12% adulthood
SPTLC2 HSAN1C ✓ 5% adulthood
WNK1 HSAN2A ✓ 2% childhood

*Preliminary-evidence gene

Pathogenic variants in the SPTLC1, NTRK1, and SPTLC2 genes account for 12%, 6% and 5% of individuals with HSAN, respectively. The DNMT1, DST, KIF1A, NGF, RETREG1, and RAB7A genes are all rare causes of HSAN. This panel also includes other genes that have been identified as causes of HSAN or other related disorders, although the exact contribution of these genes to the overall detection rate is not known and is dependent on the clinical presentation of the individual.

HSAN associated with the ATL1, ATL3, DNMT1, RAB7A, SCN11A, SPTLC1 and SPTLC2 genes is inherited in an autosomal dominant manner. Some autosomal dominant forms of HSAN are commonly caused by de novo variants. The CCT5, DST, ELP1, KIF1A, NTRK1, PRDM12, RETREG1, SCN9A and WNK1 genes are associated with autosomal recessive HSAN. NGF-associated HSAN5 is typically a severe disorder with autosomal recessive inheritance, though heterozygous carriers with mild features have been reported.

Hereditary sensory and autonomic neuropathies are a diverse group of disorders, and the penetrance varies depending on the causative gene. Incomplete penetrance has been reported for certain genes including ATL1 and SPTLC1.

The overall prevalence of HSAN is unknown. Familial dysautonomia (HSAN3) is more common in the Ashkenazi Jewish population, with an estimated incidence of 1 in 3,700. The prevalence of WNK1-associated HSAN2A is increased in the French Canadian population.

HSAN is a clinically heterogeneous group of disorders. Genetic testing may confirm a suspected diagnosis or rule out disorders with similar symptoms. A genetic diagnosis may also help predict disease progression and inform family planning.

  1. Auer-Grumbach, M. Hereditary sensory and autonomic neuropathies. Handb Clin Neurol. 2013; 115:893-906. PMID: 23931820
  2. Guelly, C, et al. Targeted high-throughput sequencing identifies mutations in atlastin-1 as a cause of hereditary sensory neuropathy type I. Am. J. Hum. Genet. 2011; 88(1):99-105. PMID: 21194679
  3. Klein, CJ, et al. Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss. Nat. Genet. 2011; 43(6):595-600. PMID: 21532572
  4. Shohat, M, Weisz, Hubshman, M. Familial Dysautonomia. 2003 Jan 21. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1180/ PMID: 20301359
  5. Kurth, I. Hereditary Sensory and Autonomic Neuropathy Type II. 2010 Nov 23. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 21089229
  6. Indo, Y. Congenital Insensitivity to Pain with Anhidrosis. 2008 Aug 05. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301726
  7. Woods, CG, et al. The phenotype of congenital insensitivity to pain due to the NaV1.9 variant p.L811P. Eur. J. Hum. Genet. 2015; 23(5):561-3. PMID: 25118027
  8. Cox, JJ, et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature. 2006; 444(7121):894-8. PMID: 17167479
  9. Dubourg, O, et al. Phenotypic and genetic study of a family with hereditary sensory neuropathy and prominent weakness. Muscle Nerve. 2000; 23(10):1508-14. PMID: 11003785
  10. Rotthier, A, et al. Mutations in the SPTLC2 subunit of serine palmitoyltransferase cause hereditary sensory and autonomic neuropathy type I. Am. J. Hum. Genet. 2010; 87(4):513-22. PMID: 20920666
  11. Lafreniere, RG, et al. Identification of a novel gene (HSN2) causing hereditary sensory and autonomic neuropathy type II through the Study of Canadian Genetic Isolates. Am. J. Hum. Genet. 2004; 74(5):1064-73. PMID: 15060842

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
ATL1 NM_015915.4
ATL3 NM_015459.4
CCT5 NM_012073.3
DNMT1 NM_001130823.1
DST NM_001723.5; NM_015548.4
ELP1 NM_003640.3
KIF1A NM_004321.6
NGF NM_002506.2
NTRK1 NM_001012331.1
PRDM12 NM_021619.2
RAB7A NM_004637.5
RETREG1 NM_001034850.2
SCN11A NM_014139.2
SCN9A NM_002977.3
SPTLC1 NM_006415.3
SPTLC2 NM_004863.3
WNK1 NM_213655.4

Clinical resources
Invitae brochure Neurology gene list
Patient resources
Patient guide: Genetic testing simplified
Test information
Forms page Specimen requirements page

References

  1. Auer-Grumbach, M. Hereditary sensory and autonomic neuropathies. Handb Clin Neurol. 2013; 115:893-906. PMID: 23931820
  2. Cox, JJ, et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature. 2006; 444(7121):894-8. PMID: 17167479
  3. Dubourg, O, et al. Phenotypic and genetic study of a family with hereditary sensory neuropathy and prominent weakness. Muscle Nerve. 2000; 23(10):1508-14. PMID: 11003785
  4. Guelly, C, et al. Targeted high-throughput sequencing identifies mutations in atlastin-1 as a cause of hereditary sensory neuropathy type I. Am. J. Hum. Genet. 2011; 88(1):99-105. PMID: 21194679
  5. Indo, Y. Congenital Insensitivity to Pain with Anhidrosis. 2008 Aug 05. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301726
  6. Klein, CJ, et al. Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss. Nat. Genet. 2011; 43(6):595-600. PMID: 21532572
  7. Kurth, I. Hereditary Sensory and Autonomic Neuropathy Type II. 2010 Nov 23. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 21089229
  8. Lafreniere, RG, et al. Identification of a novel gene (HSN2) causing hereditary sensory and autonomic neuropathy type II through the Study of Canadian Genetic Isolates. Am. J. Hum. Genet. 2004; 74(5):1064-73. PMID: 15060842
  9. Rotthier, A, et al. Mutations in the SPTLC2 subunit of serine palmitoyltransferase cause hereditary sensory and autonomic neuropathy type I. Am. J. Hum. Genet. 2010; 87(4):513-22. PMID: 20920666
  10. Shohat, M, Weisz, Hubshman, M. Familial Dysautonomia. 2003 Jan 21. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1180/ PMID: 20301359
  11. Woods, CG, et al. The phenotype of congenital insensitivity to pain due to the NaV1.9 variant p.L811P. Eur. J. Hum. Genet. 2015; 23(5):561-3. PMID: 25118027

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