Epidermolysis Bullosa with Pyloric Atresia and Plectinopathy via the PLEC Gene

Plectinopathy is caused by disruption of intermediate filament crosslinking of the cytoskeleton, affecting skin and muscle (Smith et al. 1996. PubMed ID: 8696340). Two forms of plectinopathy are known in which muscle symptoms are absent, namely Epidermolysis bullosa simplex with pyloric atresia (EBS-PA) and Epidermolysis bullosa simplex of the Ogna type (EBS-OG).

Epidermolysis bullosa simplex with pyloric atresia (EBS-PA) is a skin separation disorder characterized by congenital blistering, skin atrophy, and skin fragility. Other features in this syndrome include congenital pyloric atresia, ureterovesical stenosis, pyelonephrosis, esophageal atresia, congenital cutis aplasia and arthrogryposis (Varki et al. 2006. PubMed ID: 16473856; Fine et al. 2008. PubMed ID: 18374450; Pfendner et al. 2017. PubMed ID: 20301336). Affected neonates have blistering and extensive absence of skin on the face, scalp, trunk, and limbs (Morrell et al. 2000. PubMed ID: 11122061; Pfendner et al. 2017. PubMed ID: 20301336). Epidermolysis bullosa simplex of the Ogna type (EBS-OG) includes skin bruising in addition to the other typical skin findings. EBS-OG has been described in one family from Ogna in Norway and in one German family (Koss-Harnes et al. 2002. PubMed ID: 11851880).

Three forms of plectinopathy occur in which muscle disease is present in combination with EBS, or as the only finding. Epidermolysis bullosa with muscular dystrophy (EBS-MD) is characterized by early childhood onset of progressive muscular dystrophy and blistering skin changes. Skin blistering may be present as early as the neonatal period and additional skin findings include atrophic scarring, nail dystrophy and alopecia (Kyrova et al. 2016. PubMed ID: 28400893). Individuals with epidermolysis bullosa simplex with congenital myasthenic syndrome (EBS-MyS) have clinical features including EBS beginning in early infancy, progressive muscle weakness, and elevated serum CK levels (Maselli et al. 2011. PubMed ID: 21175599). Two different individuals presented with myasthenic symptoms at ages 3 and 9, and included progressive ocular, facial, limb, and truncal weakness, and fatigability. EMG studies demonstrated a marked decrement (Banwell et al. 1999. PubMed ID: 10446808; Selcen et al. 2011. PubMed ID: 21263134). Autosomal recessive limb-girdle muscular dystrophy, type 2Q (LGMD2Q) has been reported in one Turkish sibship (Gundesli et al. 2010. PubMed ID: 21109228). Muscle weakness was first noted in childhood. As a teenager, the proband exhibited the Gowers sign and lumbar lordosis. Muscle histology revealed variation in fiber size, internally placed nuclei, scattered necrotic fibers. Serum CK levels were elevated.

Epidermolysis bullosa with pyloric atresia is an autosomal recessive disorder caused by pathogenic variants in the ITGB4, ITGA6, and PLEC genes. EBS-OG type is an autosomal dominant disorder caused by the p.Arg2110Trp variant in the rod domain of plectin (Koss-Harnes et al. 2002. PubMed ID: 11851880). All other forms of plectinopathy are inherited in an autosomal recessive manner. The two reported EBS-MyS patients were African American and both were found to have the same c.12043dupG variant in exon 32 and differing nonsense variants in exon 31 (Selcen et al. 2011. PubMed ID: 21263134). One variant, a 9-bp deletion in exon 1 of isoform F, has thus far been reported to be causative for limb-girdle muscular dystory type 2Q (Gundesli et al. 2010. PubMed ID: 21109228).

To date, majority of the pathogenic variants reported in PLEC are nonsense, small deletions (mostly frameshift) and missense. Less common variants include splicing, gross deletions and gross duplications (Human Gene Mutation Database; Nakamura et al. 2005. PubMed ID: 15681471; Natsuga et al. 2010. PubMed ID: 20665883; Pfendner et al. 2017. PubMed ID: 20301336).

Plectin-1, encoded by PLEC, a key member of cytolinkers, interacts with different elements of the cytoskeleton and plays a crucial role in maintaining cell and tissue integrity. Plectin links the intermediate filament to the hemidesmosome and desmosome and also interacts with intergrin 64 to stable the connection between cells in the epidermis.

Pathogenic variants in PLEC account for ~15% of epidermolysis bullosa with pyloric atresia cases diagnosed by skin biopsy (Pfendner et al. 2017. PubMed ID: 20301336).

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