Junctional Epidermolysis Bullosa via the COL17A1 Gene

The collagen protein XVII (also known as BP180 and BPAG2) encoded by COL17A1 is essential for cohesion between dermal-epidermal junction, as it is a key component of hemidesmosomes needed to hold stratified epithelia to the basal membrane. Junctional epidermolysis bullosa (JEB), one of the four major types of epidermolysis bullosa (EB), is a clinically and genetically heterogeneous skin/mucosa separation disorder characterized by blister formation induced by mild trauma. COL17A1 variants often cause the mild type of JEB (non-Herlitz JEB, OMIM 226650); however, in some cases, COL17A1 null variants were also reported in the neonatal lethal form (Herlitz JEB, OMIM 226700). Variki et al. studied 20 cases with COL17A1 variants; seven of them had generalized blisters, hematuria, anemia, and growth retardation, and one of the seven patients had pseudosyndactly and wrist/ankle abnormalities, which mimic the features of dystrophic epidermolysis bullosa (Varki et al. J Med Genet 43:641-652, 2006). Other common clinical features in JEB are enamel defects, nail dystrophy, and alopecia. It should be noted that clinical manifestations overlap significantly among different types of EB, because at least 12 other genes encoding the multiprotein cohesion complex in skin contribute to epidemolysis bullosa (EB; Fine et al. J Am Acad Derm 58:931-950, 2008; Laimer et al. Dermatol Clin 28:55-60, 2010). Therefore, patients with clinically-suspected EB can be evaluated by skin biopsy to help with clinical diagnosis and direct genetic testing.

Junctional epidermolysis bullosa (JEB) is an autosomal recessive disorder caused by variants in LAMA3, LAMB3, LAMC2, and COL17A1. Variants in COL17A1 account for ~12% of reported pathogenic variants related to JEB (Pfendner et al. GeneReviews, 2008). Collagen XVII, a transmembrane protein of the hemidesmosome, contains an intracellular noncollagenous domain (exons 2 to 17), and an extracellular collagenous domain (exons 18 to 56; Giudice et al. J Invest Dermatol 99:243-250,1992; McGrath et al. Nat Genet 11:83-86, 1995; Gatalica et al. Am. J. Hum. Genet 60:352-365, 1997, Varki et al. 2006, Pfendner et al. GeneReviews, 2008). Most known variants (>80%) result in truncated proteins (nonsense, small deletions/insertions, and splicing). Two recurring variants (p.Gly803* and p.Arg1226*) comprise 7% and 10% of the reported COL17A1 variants, respectively (Kiritsi et al. J Med Genet 48:450-457, 2011). A heterozygous variant c.1880G>T (p.G627V) in COL17A1 was reported in an autosomal dominant JEB patient with an enamel defect (Almaani et al. Br J Dermatol 160:1094-1097, 2009). Variants in COL17A1 were also identified in a patient affected with epidermolysis bullosa simplex (Pasmooij et al. Br J Dermatol 151:669-674, 2004).

One study reported that the COL17A1 gene variants were found in 98.8% (85/86 alleles) of the 43 JEB patients with either reduced or absent collagen XVII expression (Kiritsi et al. J Med Genet 48:450-457, 2011).

This test provides full coverage of all coding exons of the COL17A1 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).