Junctional Epidermolysis Bullosa via the LAMB3 Gene

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 minimal or no mechanical trauma. Mutations in LAMB3 contribute to ~70% of pathogenic mutations reported in JEB cases (Herlitz JEB, OMIM#226700, ~ 70% of cases and Non-Herlitz JEB, OMIM#226650, ~30% of cases) (Kiritsi et al. J Med Genet 48:450-457, 2011; Intong et al. Clin Dermatol 30:70-77, 2012). In severe cases, erosions and granulation result in restrictions in oral, corneal, esophageal and lung tissues. Patients often die during early infancy due to complications of dehydration, anemia and sepsis. 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, clinical suspected EB patients can be evaluated by electron microscopy and immunofluorescence staining to help with clinical diagnosis and direct genetic testing.

Junctional Epidermolysis Bullosa (JEB) is an autosomal recessive disorder caused by mutations in LAMA3, LAMB3, LAMC2 and COL17A1. The LAMB3 gene codes β chain of Laminin-332 protein (also referred as Laminin5), a key component of anchoring filaments in basal membrane zone of skin required to main integrity of the skin. Most known LAMB3 mutations (>80%) resulted in prematurely terminated proteins. One study showed that the mutation c.1903C>T, p. Arg635Stop explains ~40% of mutant alleles identified in LAMB3 gene (Varki et al. J Med Genet 43:641-652, 2006). Also, ethnicity-related LAMB3 mutations were described (such as p.Arg635Stop and c.727C>T, p.Gln243Stop in Europeans, c.124C>T, p.Arg42Stop in Hispanic and African Americans). Large deletions/duplications were seen in less than 1% of cases (Varki et al. J Med Genet 43:641-652, 2006, Pfendner et al, GeneReviews, 2008). Furthermore, germline mosacism and uniparental disomy were reported (Pulkkinen and Uitto. Matrix Biol. 18:29-42, 1999; Pfendner et al. GeneReviews, 2008).

Detection rate should be very high in biopsy confirmed JEB patients with either reduced or absent Laminin-332 expression. As reported, LAMB3 mutations account for more than 80% of JEB related to mutations in Laminin-332 three genes and ~70% of all disease causing mutations identified in JEB.

This test provides full coverage of all coding exons of the LAMB3 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.