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.
ATL1 ATL3 DNMT1 DST ELP1 KIF1A NGF NTRK1 RAB7A RETREG1 SCN11A SCN9A SPTLC1 SPTLC2 WNK1
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.
ATL1 ATL3 DNMT1 DST ELP1 KIF1A NGF NTRK1 RAB7A RETREG1 SCN11A SCN9A SPTLC1 SPTLC2 WNK1
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
For a broader analysis of the genetics of hereditary neuropathies:
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.
Gene | HSAN/HSN subtype or related disorder | Inheritance | Proportion of HSAN Cases | Typical age of onset | |
---|---|---|---|---|---|
Autosomal dominant | Autosomal 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.
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 |