Ectodermal Dysplasia/Short Stature Syndrome and Deafness, Autosomal Dominant 28 (DFNA28) via the GRHL2 Gene

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).

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).

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.

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).