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Hereditary Sensory and Autonomic Neuropathy Type II

Synonyms: Hereditary Sensory and Autonomic Neuropathy Type 2 (HSAN2), HSANII

, MD.

Author Information and Affiliations

Initial Posting: ; Last Update: April 1, 2021.

Estimated reading time: 17 minutes

Summary

Clinical characteristics.

Hereditary sensory and autonomic neuropathy type II (HSAN2) is characterized by progressively reduced sensation to pain, temperature, and touch. Onset can be at birth and is often before puberty. The sensory deficit is predominantly distal with the lower limbs more severely affected than the upper limbs. Over time sensory function becomes severely reduced. Unnoticed injuries and neuropathic skin promote ulcerations and infections that result in spontaneous amputation of digits or the need for surgical amputation. Osteomyelitis is common. Painless fractures can complicate the disease. Autonomic disturbances are variable and can include hyperhidrosis, tonic pupils, and urinary incontinence in those with more advanced disease.

Diagnosis/testing.

The diagnosis of HSAN2 is established in a proband with suggestive clinical and electrophysiologic findings and biallelic pathogenic variants in one of four genes: KIF1A, RETREG1 (FAM134B), SCN9A, or WNK1.

Management.

Treatment of manifestations: Treatment is symptomatic and often involves a team including neurologists, orthopedic surgeons, and physiotherapists. Training in the care of the sensory-impaired limb, often in a diabetic foot care clinic, is important and includes self-examination – especially of the feet – for any signs of trauma. To prevent osteomyelitis, and hence the need for amputation, wounds require cleaning and protection along with antiseptic treatment. To prevent callous formation, the skin of neuropathic limbs requires hydration and lipid-based unguents. Appropriate shoes and socks are recommended.

Surveillance: The feet should be inspected daily for injuries or sources of wear. Annual follow up in centers with comprehensive care of diabetics and/or persons with Charcot-Marie-Tooth neuropathy is recommended.

Agents/circumstances to avoid: Ill-fitting shoes or other sources of trauma to the feet or hands (e.g., use protective gloves when handling hot items when cooking.)

Genetic counseling.

HSAN2 is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an HSAN2-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the HSAN2-causing pathogenic variants in the family are known, carrier testing of at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible.

GeneReview Scope

Hereditary Sensory and Autonomic Neuropathy Type II (HSAN2): Included Phenotypes 1
  • KIF1A-related HSAN2 (HSAN2C)
  • RETREG1-related HSAN2 (HSAN2B)
  • SCN9A-related HSAN2 (HSAN2D)
  • WNK1-related HSAN2 (HSAN2A)

For synonyms and outdated names see Nomenclature.

1.

For other genetic causes of these phenotypes, see Differential Diagnosis.

Diagnosis

No consensus clinical diagnostic criteria for hereditary sensory and autonomic neuropathy type II (HSAN2) have been published.

Suggestive Findings

Hereditary sensory and autonomic neuropathy type II (HSAN2) should be suspected in individuals with the following clinical and electrophysiologic findings and family history.

Clinical findings

  • Congenital or early-onset (1st to 2nd decade) sensory deficit
  • Sensory loss affecting all modalities
  • Ulcerations of hands/feet often requiring amputation
  • Acral mutilations
  • Painless fractures and neuropathic arthropathy in some
  • Varying degree of autonomic involvement: hyperhidrosis, urinary incontinence, and slow pupillary reaction to light

Electrophysiologic findings

  • Reduced/absent sensory nerve action potentials
  • Preserved or reduced motor nerve conduction velocities (NCV)
  • Variably reduced compound muscle action potentials (CMAP)

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of HSAN2 is established in a proband with suggestive clinical and electrophysiologic findings and biallelic pathogenic variants in one of four genes: KIF1A, RETREG1 (FAM134B), SCN9A, or WNK1. (See Table 1.)

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of a pure sensory neuropathy has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

When the phenotypic and electrophysiologic findings suggest the diagnosis of HSAN2, the molecular genetic testing approach is use of a multigene panel.

A hereditary sensory and autonomic neuropathy multigene panel that includes some or all of the genes listed in Table 1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Hereditary Sensory and Autonomic Neuropathy Type II (HSAN2)

Gene 1, 2Proportion of HSAN2 Attributed to Pathogenic Variants in GeneProportion of Pathogenic Variants 3 Detectable by Method
Sequence
analysis 4
Gene-targeted deletion/duplication analysis 5
KIF1A Too few case reports for conclusive assessment100% 6None reported 6
RETREG1 (FAM134B) 100% 6None reported 6
SCN9A >90% 6A few cases 6, 7
WNK1 >90% 6Whole-gene deletion in 1 family 8; intragenic deletion 9
1.

Genes are listed in alphabetic order.

2.

See Table A. Genes and Databases for chromosome locus and protein.

3.

See Molecular Genetics for information on variants detected in these genes.

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2017]

7.

And Author, unpublished data

8.
9.

Author, unpublished data

Clinical Characteristics

Clinical Description

The published clinical descriptions of hereditary sensory and autonomic neuropathy type II (HSAN2) are inconsistent, possibly in part as a result of reports that lack molecular genetic confirmation of the diagnosis. Clinically, WNK1-related HSAN2 (HSAN2A), RETREG1 (FAM134B)-related HSAN2 (HSAN2B), and KIF1A-related HSAN2 (HSAN2C) appear to be very similar.

Autonomic dysfunction may be more pronounced in RETREG1-related neuropathy, and individuals with KIF1A-related HSAN2 also showed distal muscle weakness. SCN9A-related HSAN2 was reported in two families [Yuan et al 2013].

Table 2.

Hereditary Sensory and Autonomic Neuropathy Type II (HSAN2): Gene-Phenotype Correlations

FeatureAssociated Gene (HSAN2 Subtype)
WNK1 (HSAN2A)RETREG1 (HSAN2B)KIF1A (HSAN2C)SCN9A (HSAN2D)
Sensory deficit++++++++++++
Autonomic dysfunction++++++++
Distal motor involvement++++-
+

++= most common; ++= less common; += rare; -= not observed

In molecularly confirmed HSAN2, onset is typically in the first two decades (often before puberty). It is characterized by progressive numbness of the hands and feet, together with reduced sensation to pain, temperature, and touch. The sensory deficit is predominantly distal with the lower limbs more severely affected than the upper limbs. Over time, sensory function becomes severely reduced.

Neuropathic skin tends to produce excessive keratin and hyperkeratosis that may be forced down into the deeper layers of soft tissue and/or may crack, promoting ulcerations and infections that result in spontaneous amputation of digits or the need for surgical amputation. Osteomyelitis is common.

Secondary muscle atrophy and Charcot joints may occur. Painless fractures can complicate the disease.

Intellectual development is usually normal but can be impaired, especially in KIF1A-related HSAN2.

Sweating and tearing are usually normal but hyperhidrosis is present in some cases. Tonic pupils are observed. With progression of the disease urinary incontinence is reported.

Histopathology. Sural nerve biopsy shows signs of an axonal sensory neuropathy, pronounced absence of (small) myelinated fibers, and decreased unmyelinated fibers. Additionally, loss of large myelinated fibers may be seen in those with HSAN2D.

Genotype-Phenotype Correlations

No genotype-phenotype correlations are known. Inter- and intrafamilial phenotypic variability is reported.

Nomenclature

HSAN2 has also been reported as the following:

  • Morvan's disease
  • Congenital sensory neuropathy
  • Neurogenic acroosteolysis
  • Hereditary sensory radicular neuropathy

Dyck originally proposed five different HSAN types on the basis of clinical manifestations and nerve biopsy specimens [Dyck 1993]. More recently, genetic and additional phenotypic heterogeneity has been described [Verhoeven et al 2006], suggesting a need for a detailed classification based on the underlying gene defects [Rotthier et al 2012, Schwartzlow & Kazamel 2019].

Prevalence

The worldwide prevalence of HSAN2 is unknown. Several hundred affected individuals have been reported.

For comparison, the overall prevalence of the closely related hereditary motor and sensory neuropathies (HMSN or Charcot-Marie-Tooth neuropathy) is about 30:100,000, and hereditary sensory and autonomic neuropathies (HSAN) occur with markedly lower frequency.

See Table 5 for WNK1 founder variants identified in eastern Canada [Roddier et al 2005] and Japan [Yuan et al 2017].

Differential Diagnosis

HSAN is a heterogeneous group of disorders in which pathogenic variants in other genes lead to overlapping clinical phenotypes. The distinction between HSAN and clinically similar congenital insensitivity to pain (CIP) is inconsistent. A list of genes implicated in other types of HSAN and/or CIP is provided in Table 4.

Table 4.

Disorders of Interest in the Differential Diagnosis of Hereditary Sensory and Autonomic Neuropathy Type II (HSAN2)

GeneHSAN ClassificationMOITypical Age at OnsetClinical (Distinguishing) FeaturesReference
ATL1 HSAN1ADAdulthoodPainless ulcers, fractures; involvement of upper motor neurons describedSee HSN1D or allelic Spastic Paraplegia 3A.
ATL3 HSAN1ADAdulthoodPainless ulcers, fractures; spasticity in some persons; severely delayed wound healing; multiple fractures of foot skeletonOMIM 615632
CLTCL1 Not classifiedARCongenitalCIP, inability to feel touch, IDOMIM 601273
DNMT1 HSAN1ADAdulthoodLoss of pain, ulcers; sensorineural hearing loss, progressive dementia, sensory ataxia DNMT1-Related Disorder
DST HSAN6ARCongenitalAutonomic involvement; alacrimia, feeding difficulties, contractures, hypomimia, severeDD/IDOMIM 614653
ELP1 HSAN3ARCongenitalPredominant autonomic neuropathy; alacrimia, gastrointestinal dysfunction, vomiting, cardiovascular instability, blood pressure fluctuations, autonomic crises, scoliosis Familial Dysautonomia
FAAHP1 (FAAH-OUT)CIPAD
AR
CongenitalPain insensitivity & impaired anxietyOMIM 618377
FLVCR1 ARCongenitalPainless injuries, psychomotor delay, anemia Chiabrando et al [2016]
NGF HSAN5ARCongenitalSee phenotype of HSAN4. Congenital Insensitivity to Pain Overview
NTRK1 HSAN4ARCongenitalCIP w/anhidrosis, self-mutilations (biting the tongue, biting of fingertips), fever episodes (lack of sweat gland innervation), painless fractures, variable degree of ID, corneal lesions NTRK1 Congenital Insensitivity to Pain with Anhidrosis
PRDM12 HSAN8ARCongenitalPain insensitivity, facial injuries, sweating usually preserved, ID less common Congenital Insensitivity to Pain Overview
RAB7A ADAdulthoodStrong motor involvement, also classified as CMT2B Charcot-Marie-Tooth Hereditary Neuropathy Overview
SCN11A CIP/HSAN7ADCongenitalPredilection for skin ulcers to cervical region, pruritus, intestinal dysmotility, delayed motor development, joint hypermobility Congenital Insensitivity to Pain Overview
SPTLC1 HSAN1ADAdulthoodLoss of pain (may be assoc w/lancinating pain); ulcerations, mutilations, mild motor involvement (may be pronounced in some persons) SPTLC1-Related Hereditary Sensory Neuropathy
SPTLC2 HSAN1ADAdulthoodSimilar to SPTLC1-HSNOMIM 613640
ZFHX2 CIPADChildhoodHyposensitivity to painful thermal & capsaicin stimulation & painless injuries Congenital Insensitivity to Pain Overview

Adapted from Cox et al [2020], Table 1.

AD = autosomal dominant; AR = autosomal recessive; CIP = congenital insensitivity to pain; CMT = Charcot-Marie-Tooth hereditary neuropathy; DD = developmental delay; HSAN = hereditary sensory and autonomic neuropathy; HSN = hereditary sensory neuropathy; ID = intellectual disability; MOI = mode of inheritance

Other genetic disorders to consider. Disorders accompanied by self-mutilating behavior resemble some aspects of the congenital forms of HSAN including Lesch-Nyhan disease (see HPRT1 Disorders) or untreated phenylketonuria.

Management

No clinical practice guidelines for hereditary sensory and autonomic neuropathy type II (HSAN2) have been published.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with hereditary sensory and autonomic neuropathy type II (HSAN2), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:

  • Neurologic examination to determine extent of sensory loss and involvement of autonomic and motor nervous system
  • Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of HSAN2 in order to facilitate medical and personal decision making

Treatment of Manifestations

Treatment is symptomatic and often involves a multidisciplinary team including neurologists, orthopedic surgeons, and physiotherapists.

Training in the care of the sensory-impaired limb is important and includes self-examination – especially of the feet – for any signs of trauma. A diabetic clinic is a good source of advice. Appropriate shoes and socks are recommended.

It is best to prevent callous formation in neuropathic skin; once present, calluses should be treated with hydration and lipid-based unguents to prevent cracking and may require medical consultation.

Cleaning and protection of wounds on neuropathic limbs in combination with antiseptic treatment to eradicate infections helps prevent osteomyelitis and the possible future need to amputate a limb.

Surveillance

The feet should be inspected daily for injuries and sources of wear.

Affected individuals should be followed annually by centers with comprehensive care, such as those for diabetic foot care and/or Charcot-Marie-Tooth neuropathy, also known as hereditary motor and sensory neuropathy.

Agents/Circumstances to Avoid

Avoid ill-fitting shoes or other sources of trauma to the feet or hands (e.g., use protective gloves when handling hot items when cooking).

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of at-risk sibs in order to identify those who will develop sensory loss and would benefit from measures to prevent injury to limbs and/or self-mutilation.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Hereditary sensory and autonomic neuropathy type II (HSAN2) is an autosomal recessive disorder caused by biallelic KIF1A (HSAN2C), RETREG1 (HSAN2B), SCN9A (HSAN2D), or WNK1 (HSAN2A) pathogenic variants.

Risk to Family Members

Parents of a proband

  • In most families, both parents of an affected child are carriers (i.e., heterozygotes) for a KIF1A, RETREG1 (FAM134B), SCN9A, or WNK1 pathogenic variant.
  • In rare families, only one parent is heterozygous for a pathogenic variant and the child has HSAN2 as the result of uniparental isodisomy and consequent homozygosity for the HSAN2-causing pathogenic variant from the carrier parent. (Uniparental isodisomy has been reported in a child with RETREG1-related HSAN2 [Park et al 2019].)
  • Accurate recurrence risk counseling relies on carrier testing of both parents to determine if both are heterozygous for an HSAN2-causing pathogenic variant. If carrier testing detects the pathogenic variant in only one parent:
    • And the child appears to have homozygous HSAN2-causing pathogenic variants, possible explanations include a large deletion on one allele (if not previously tested for) and uniparental isodisomy [Park et al 2019]);
    • And the child has compound heterozygous HSAN2-causing pathogenic variants, the child may theoretically have one inherited pathogenic variant and one de novo pathogenic variant. (De novo variants are known to occur at a low but appreciable rate in autosomal recessive disorders [Jónsson et al 2017].)
  • Heterozygotes (carriers) are asymptomatic except for the report of increased sensitivity to thermal stimuli in individuals who are heterozygous for an HSAN2-related WNK1 pathogenic variant [Loggia et al 2009].

Sibs of a proband

  • If both parents are known to be heterozygous for an HSAN2-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier.
  • Significant clinical variability between affected sibs can be observed.
  • If the proband has HSAN2 as the result of uniparental isodisomy, if only one parent is heterozygous for an HSAN2-causing pathogenic variant, and if neither parent has a chromosome rearrangement, each sib of an affected individual has at conception a 50% chance of being a carrier and an approximately 50% chance of being unaffected and not a carrier. (The risk to sibs of a proband of being affected is unknown but is presumed to be <1%.)
  • Heterozygotes (carriers) are typically asymptomatic (see exception in Parents of a proband).

Offspring of a proband. Unless an individual with HSAN2 has children with an affected individual or a carrier (see Prevalence), his/her offspring will be obligate heterozygotes (carriers) for an HSAN2-causing pathogenic variant.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier of an HSAN2-causing pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the HSAN2-causing pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the HSAN2-causing pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Hereditary Sensory and Autonomic Neuropathy Type II: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Hereditary Sensory and Autonomic Neuropathy Type II (View All in OMIM)

201300NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE IIA; HSAN2A
243000INDIFFERENCE TO PAIN, CONGENITAL, AUTOSOMAL RECESSIVE; CIP
601255KINESIN FAMILY MEMBER 1A; KIF1A
603415SODIUM VOLTAGE-GATED CHANNEL, ALPHA SUBUNIT 9; SCN9A
605232PROTEIN KINASE, LYSINE-DEFICIENT 1; WNK1
613114RETICULOPHAGY REGULATOR 1; RETREG1
613115NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE IIB; HSAN2B
614213NEUROPATHY, HEREDITARY SENSORY, TYPE IIC; HSN2C

Molecular Pathogenesis

Mechanism of disease causation for all genes. Given the spectrum of pathogenic variant types in the HSAN2-related genes (nonsense variants, frameshift variants, and splice-site variants are part of the mutation spectrum), biallelic loss of function can be assumed.

Gene-specific laboratory technical considerations. Alternate splicing of WNK1 results in the inclusion of exon 10 ("HSN2" exon). HSN2 was first reported as a single-exon gene located in intron 8 of WNK1, with both genes transcribed from the same strand [Lafreniere et al 2004]. Subsequently, HSN2 was found to be an alternatively spliced exon present in a nervous system-specific isoform of WNK1 [Shekarabi et al 2008]. The majority of HSAN2-causing variants in WNK1 reported to date are frameshift or nonsense variants in exon 10. Because pathogenic variants in other exons of WNK1 may also contribute to the HSAN2A phenotype, sequence analysis of all known exons from genomic DNA may be necessary if only one pathogenic variant is found in exon 10. Note: Homozygous or compound heterozygous null alleles affecting all WNK1 isoforms are thought to be embryonically lethal.

Table 5.

Notable WNK1 Pathogenic Variants

GeneReference SequencesDNA Nucleotide Change 1 (Alias 2)Predicted Protein Change 1 (Alias 2)Comment [Reference]
WNK1 NM_213655​.5
NP_998820​.3
c.2952delA (594delA)p.Glu984AspfsTer10
(Glu198AspfsTer10)
French Canadian founder variants [Roddier et al 2005]
c.3276dupA
(918_919insA)
p.Ser1093IlefsTer13
(Ser307IlefsTer13)
c.3301C>T
(943C>T)
p.Gln1101Ter
(Gln315Ter)
c.3492dupTp.Asp1165TerJapanese founder variant [Yuan et al 2017]

Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Nucleotide and amino acid nomenclature is based on the reference sequences for WNK1 isoform wnk1tv3. In this transcript, the "HSN2" exon is number 10. All of the pathogenic variants in this table are in exon 10 (see Gene-specific laboratory technical considerations).

2.

The alias nucleotide and amino acid changes are derived from Lafreniere et al [2004] based on the original identification and numbering of the purported gene HSN2 (UCSC HSN2 uc001qiq​.2 protein sequence). The first codon of the HSN2 exon of WNK1 is located 12 amino acids 3´ of the initially supposed Met start-codon of the single-exon HSN2 transcript; pathogenic variants in parentheses in Table 5 and in Lafreniere et al [2004] are numbered accordingly.

Chapter Notes

Author Notes

Website: www.ukaachen.de/en/clinics-institutes/institute-of-human-genetics

The Institute of Human Genetics offers HSAN testing on a research basis via the ENISNIP consortium. For further information regarding massive parallel sequencing of HSAN-relevant genes, please contact ikurth@ukaachen.de.

Revision History

  • 1 April 2021 (bp) Comprehensive update posted live
  • 19 February 2015 (me) Comprehensive update posted live
  • 3 November 2011 (ik) Revision: added HSAN2C, caused by KIF1A pathogenic variants
  • 23 November 2010 (me) Review posted live
  • 14 July 2010 (ik) Original submission

References

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