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Ectodermal Dysplasia/Short Stature Syndrome and Deafness, Autosomal Dominant 28 (DFNA28) via the GRHL2 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
11367 GRHL2 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
11367GRHL281479 81479(x2) $890 Order Options and Pricing

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 backbone).

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

Turnaround Time

18 days on average for standard orders or 13 days 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.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Ben Dorshorst, PhD

Clinical Features and Genetics

Clinical Features

Nonsyndromic hearing loss is characterized by difficulty or inability to hear that is not associated with any visible defects involving the external ear, other organs, or any other medical condition. Nonsyndromic hearing loss may be associated with abnormalities involving the middle ear and/or the inner ear (Ciuman 2013; Dodson et al. 2011; Hilgert et al. 2009). At least 70% of cases involving hearing loss are nonsyndromic (Van Camp et al. 1997).

Nonsyndromic hearing loss and deafness due to pathogenic variants in the GRHL2 gene involves postlingual, bilateral, mild to moderate, progressive sensorineural hearing impairment. Initially all frequencies are affected, progressing to severe hearing loss in the high frequencies by the fifth decade. Age of onset is highly variable and can be as early as the first decade (Peters et al. 2002; Vona et al. 2013).

Pathogenic variants in GRHL2 are also associated with ectodermal dysplasia/short stature syndrome, an autosomal recessive skin disorder characterized by short stature, nail dystrophy or nail loss, marginal palmoplantar keratoderma, hypodontia, enamel hypoplasia, oral hyperpigmentation, and dysphagia. Affected individuals may also have sensorineural deafness or bronchial asthma (Petrof et al. 2014).

Genetics

DFNA28 is an autosomal dominant hearing disorder that is caused by pathogenic sequence variants in the grainyhead like transcription factor 2 (GRHL2) gene, which is located on chromosome 8q22.3. The GRHL2 gene spans 181 kb and consists of 16 coding exons that produce a 625 amino acid protein. The GHRL2 gene is expressed in the embryonic and postnatal mouse cochlear duct (Peters et al. 2002). The GHRL2 protein is a transcription factor that is involved in the differentiation and maintenance of epithelial cells (Werth et al. 2010). Only one splicing and one small insertion variant in GRHL2 have been reported as pathogenic for hearing loss (Peters et al. 2002; Vona et al. 2013).

Ectodermal dysplasia/short stature syndrome is an autosomal recessive skin disorder that is also caused by pathogenic sequence variants in the GRHL2 gene. Two missense variants in GRHL2 have been reported to cause ectodermal dysplasia/short stature syndrome, both detected in unrelated consanguineous Kuwaiti families (Petrof et al. 2014).

Clinical Sensitivity - Sequencing with CNV PGxome

The clinical sensitivity of this sequencing test is not precisely known. Only one splicing and one small insertion variant in GRHL2 have been reported as pathogenic for hearing loss (Peters et al. 2002; Vona et al. 2013). Two missense variants in GRHL2 have also been reported to cause ectodermal dysplasia/short stature syndrome (Petrof et al. 2014). Analytical sensitivity should be high because all reported variants are detectable by sequencing.

The clinical sensitivity of copy number variant detection is unknown. In 79 patients with a clinical diagnosis of sensorineural hearing loss, two deletion/duplication variants in GRHL2 were detected (Ji et al. 2014). However, the pathogenicity of these variants was not fully evaluated and they were of a size (~100 bp) more likely to be detected by sequencing. No other deletion or duplication variants associated with GRHL2 have been reported as pathogenic for hearing loss. No large deletion or duplication variants associated with GRHL2 have been reported as pathogenic for ectodermal dysplasia/short stature syndrome.

Testing Strategy

This test provides full coverage of all coding exons of the GRHL2 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

Nonsyndromic hearing loss and deafness due to variants in the GRHL2 gene is suspected in individuals with the following: postlingual, bilateral, mild to moderate, progressive sensorineural hearing impairment; no related systemic findings identified by medical history and physical examination; and/or a family history of nonsyndromic hearing loss consistent with autosomal dominant inheritance.

Ectodermal dysplasia/short stature syndrome due to variants in the GRHL2 gene is suspected in individuals with the following: short stature, nail dystrophy or nail loss, marginal palmoplantar keratoderma, hypodontia, enamel hypoplasia, oral hyperpigmentation, and dysphagia; and/or sensorineural deafness or bronchial asthma; and a suspected autosomal recessive mode of inheritance. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in GRHL2.

Gene

Official Gene Symbol OMIM ID
GRHL2 608576
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Citations

  • Ciuman R.R. 2013. Medical Science Monitor. 19: 1195-210. PubMed ID: 24362017
  • Dodson K.M. et al. 2011. American Journal of Medical Genetics. Part A. 155A: 993-1000. PubMed ID: 21465647
  • Hilgert N. et al. 2009. Mutation Research. 681: 189-96. PubMed ID: 18804553
  • Ji H. et al. 2014. Bmc Ear, Nose, and Throat Disorders. 14: 9. PubMed ID: 25342930
  • Peters L.M. et al. 2002. Human Molecular Genetics. 11: 2877-85. PubMed ID: 12393799
  • Petrof G. et al. 2014. American Journal of Human Genetics. 95: 308-14. PubMed ID: 25152456
  • Van Camp G. et al. 1997. American Journal of Human Genetics. 60: 758-64. PubMed ID: 9106521
  • Vona B. et al. 2013. American Journal of Medical Genetics. Part A. 161A: 2060-5. PubMed ID: 23813623
  • Werth M. et al. 2010. Development. 137: 3835-45. PubMed ID: 20978075

Ordering/Specimens

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


Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

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