Dystrophic Epidermolysis Bullosa (DEB) via the COL7A1 Gene

Dystrophic Epidermolysis Bullosa (DEB) is a clinically heterogeneous skin separation disorder caused by mutations in the COL7A1 gene. DEB is characterized by blister formation induced by mild trauma. Autosomal recessive DEB (RDEB; OMIM#226600) can be further divided into severe generalized RDEB (also called Hallopeau-Siemens type) and generalized, not severe RDEB (also called non-Hallopeau-Siemens type). Severe generalized RDEB is the most severe form of DEB, where blisters may develop in the neonatal period and affect the whole body. Erosions and fusions can lead to restrictions in oral, corneal, esophageal, and lung tissue. Pseudosyndactly caused by extensive blistering and erosion can be a hallmark of severe generalized RDEB. Autosomal dominant DEB (DDEB; OMIM#131750) is the second most common subtype of epidermolysis bullosa, where the dystrophic nails may be the only manifestation in some of the DDEB patients, and blisters tend to be mild and localized to hands, knees and elbows. DEB patients are at high risk to develop squamous cell carcinoma (Fine et al. J Am Acad Dermatol 58: 931- 950, 2008; Pfendner et al. GeneReview, 2010; Intong et al. Clinics in Dermatology 30:70-77, 2012). In addition to DEB, mutations in COL7A1 also cause other DEB-related disorders including epidermolysis bullosa, BART type (OMIM#132000), epidermolysis bullosa pruriginosa (OMIM#604129), epidermolysis bullosa, pretibial (OMIM#131850), toenail dystrophy, isolated (OMIN#607523) and transient bullous of the newborn (OMIM#131705).

Collagen VII, a homotrimer of three α1 (VII) chains, is the major component of anchoring fibrils in the basal membrane zone of skin and cornea. It contains a central collagenous triple helical domain which is flanked by a large amino terminus (NC1) and a small carboxyl terminus (NC2) noncollagenous domain. Through the NC1 domain, Collagen VII interacts with various adhesive proteins including fibronectin, laminin 5 and type I and type IV collagens to bridge the dermo-epidermal connection (Keene et al. J of Cell Biology 104:611-621, 1987; Chen et al., J Bio Chem 272:14516-14522, 1997). The penetrance of DEB is less than 100% (Hilal et al. Nat Genet 5: 287-293, 1993; Christiano et al. Nat Genet 4: 62, 1993; Pulkkinen and Uitto. Matrix Biology 18:29-42, 1999; Varki et al. J Med Genet 44:181–192, 2007 and Pfendner et al. GeneReview, 2010). To date, more than 600 distinct mutations have been documented in (Human Gene Mutation Database). Causative mutations include missense, nonsense, splicing mutations and small insertions/deletions. Only 10 large genome rearrangements involving COL7A1 were reported. In addition, one DEB case with maternal COL7A1 UPD was reported (Fassihi et al. J Invest Dermatol 126, 2039–2043, 2006). Approximately 75% of the DDEB mutations occur in exons 73–75; while RDEB are caused by truncated mutations scattered throughout COL7A1 (Varki et al., 2007; Pfendner et al. GeneReview, 2010).

Mutations in the COL7A1 gene can be found in ~95% of DEB patients diagnosed with skin biopsy (Pfendner et al. GeneReviews, 2010).

To date, more than 600 distinct mutations have been documented in COL7A1 (Human Gene Mutation Database). Causative mutations include missense, nonsense, splicing mutations and small insertions/deletions. Only 10 large genome rearrangements involving COL7A1 were reported. In addition, one DEB case with maternal COL7A1 UPD was reported (Fassihi et al. J Invest Dermatol 126, 2039–2043, 2006).

This test provides full coverage of all coding exons of the COL7A1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.