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Netherton Syndrome via the SPINK5 Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
SPINK5 81479 81479,81479 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
11709SPINK581479 81479,81479 $990 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing platform).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing platform).

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Turnaround Time

3 weeks on average for standard orders or 2 weeks on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.


Genetic Counselors


  • Megan Piazza, PhD, FACMG

Clinical Features and Genetics

Clinical Features

Netherton Syndrome (NS) is a congenital disorder hallmarked by erythroderma, a “bamboo hair” appearance due to hair shaft anomalies, and atopic diathesis. An estimated 1 in 200,000 people are affected worldwide, and NS accounts for up to 18% of congenital erythrodermas (Pruszkowski et al 2000). NS presents during the neonatal period with life threatening complications including hypernatremia dehydration, hypothermia, weight loss, bronchopneumonia, sepsis, and failure to thrive. Symptoms often improve with increased age, but most children remain underweight and short in stature. Atopic symptoms may include eczema, dermatitis, hay fever, pruritus, angioedema, urticarial, hyper immunoglobulin E levels, and eosinophilia. Ichthyosis linearis circumflexa, which consists of double edged scaling on the skin, is a common dermatologic finding in children older than two years of age (Sprecher et al. 2001; Bitoun et al. 2002). In some cases, bamboo hair (trichorrhexis invaginata) is not apparent until after two years of age, and may not be present in all hair follicles making diagnosis difficult. Genetic testing is helpful in the differential diagnosis of NS from other hyper IgE syndromes, erythrodermas, and acrodermatitis enteropathica, and Omenn syndrome.


NS is inherited in an autosomal recessive manner through pathogenic variants in the SPINK5 gene. Over 75 pathogenic variants have been reported to date, and are all truncating with nonsense, splice alterations, and small insertions/deletions resulting in frameshifts being reported. Variants are typically private, fully penetrant, and occur throughout the coding region (Sprecher et al. 2001; Bitoun et al. 2002; Raghunath et al. 2004). Gross deletion of the SPINK5 gene has been reported in one case (Hachem et al. 2006). The SPINK5 gene encodes a lympho-epithelial Kazal-type inhibitor called LEKTI. LEKTI interacts with several proteases to regulate skin barrier homeostasis and inflammatory responses (Fortugno et al. 2012).

Clinical Sensitivity - Sequencing with CNV PGxome

In two separate studies of patients with a confirmed NS diagnosis, pathogenic variants in the SPINK5 gene were found in 14 of 19, and 21 of 21 individuals respectively (Sprecher et al. 2001; Bitoun et al. 2002).

Testing Strategy

This test provides full coverage of all coding exons of the SPINK5 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).

Indications for Test

Candidates for testing include newborns with erythroderma and abnormal looking scalp hair, and cutaneous infections. Skin biopsy showing ichthyosis linearis circumflexa, light microscopy confirming “bamboo hair” appearance, and hyper IgE levels are common laboratory findings (Sprecher et al. 2001; Bitoun et al. 2002). This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in SPINK5.


Official Gene Symbol OMIM ID
SPINK5 605010
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Netherton Syndrome AR 256500


  • Bitoun E, Chavanas S, Irvine AD, Lonie L, Bodemer C, Paradisi M, Hamel-Teillac D, Ansai S, Mitsuhashi Y, Taïeb A, Prost Y de, Zambruno G, Harper JI, Hovnanian A. 2002. Netherton syndrome: disease expression and spectrum of SPINK5 mutations in 21 families. J. Invest. Dermatol. 118: 352–361. PubMed ID: 11841556
  • Fortugno P, Bresciani A, Paolini C, Pazzagli C, El Hachem M, D’Alessio M, Zambruno G. 2011. Proteolytic activation cascade of the Netherton syndrome–defective protein, LEKTI, in the epidermis: implications for skin homeostasis. Journal of Investigative Dermatology 131: 2223–2232. PubMed ID: 21697885
  • Hachem J-P, Wagberg F, Schmuth M, Crumrine D, Lissens W, Jayakumar A, Houben E, Mauro TM, Leonardsson G, Brattsand M, Egelrud T, Roseeuw D, Clayman GL, Feingold KR, Williams ML, Elias PM. 2006. Serine protease activity and residual LEKTI expression determine phenotype in Netherton syndrome. Journal of investigative dermatology 126: 1609–1621. PubMed ID: 16601670
  • Pruszkowski A, Bodemer C, Fraitag S, Teillac-Hamel D, Amoric JC, Prost Y de. 2000. Neonatal and infantile erythrodermas: a retrospective study of 51 patients. Arch Dermatol 136: 875–880. PubMed ID: 10890989
  • Raghunath M, Tontsidou L, Oji V, Aufenvenne K, Schürmeyer-Horst F, Jayakumar A, Ständer H, Smolle J, Clayman GL, Traupe H. 2004. SPINK5 and Netherton syndrome: novel mutations, demonstration of missing LEKTI, and differential expression of transglutaminases. Journal of investigative dermatology 123: 474–483. PubMed ID: 15304086
  • Sprecher E, Chavanas S, DiGiovanna JJ, Amin S, Nielsen K, Prendiville JS, Silverman R, Esterly NB, Spraker MK, Guelig E, de Luna ML, Williams ML, Buehler B, Siegfried EC, Van Maldergem L, Pfendner E, Bale SJ, Uitto J, Hovnanian A, Richard G. 2001. The spectrum of pathogenic mutations in SPINK5 in 19 families with Netherton syndrome: implications for mutation detection and first case of prenatal diagnosis. Journal of investigative dermatology 117: 179–187. PubMed ID: 11511292


Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page

If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.

Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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Note: acceptable specimen types are whole blood and DNA from whole blood only.
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