Hereditary Lymphedema via the GJC2 Gene

Primary lymphedema is a chronic condition of lymphatic drainage failure that arises from developmental or functional abnormalities of the lymphatic system. Lymphedema type 1C (OMIM 613480) presents most commonly with lower limb lymphedema. Onset ranges from birth to 40 years with most experiencing symptoms within the first or second decades (Ostergaard et al. J Med Genet 48:251-255, 2011). The severity of the disease varies from mild lower limb swelling to edema in all four limbs. More severe cases may involve skin infections and cellulitis (Ferrell et al. Am J Human Genet 86:943-948, 2010; Ostergaard et al. J Med Genet 48:251-255, 2011). Variants in the GJC2 gene are also associated with Pelizaeus-Merzbacher-like disease (PMLD, OMIM 608804). Patients with PMLD have reduced formation of myelin in the brain (Van der Knaap et al. Radiology 213:121-133, 1999) and present with nystagmus, hypotonia, motor delay, cerebellar ataxia, and spasticity (Uhlenberg et al. Am J Hum Genet 75:251-260, 2004).

Variants in the GJC2 gene associated with lymphedema are inherited in an autosomal dominant manner (Ferrell et al. Am J Human Genet 86:943-948, 2010), whereas variants in the GJC2 gene associated with PMLD are inherited in an autosomal recessive manner (Uhlenberg et al. Am J Hum Genet 75:251-260, 2004). The single coding exon of the GJC2 gene encodes a member of the connnexin family of proteins, connexin 47 (Cx47). Cx47 is expressed in lymphatic endothelial cells and in oligodendrocytes. Hexamers of connexin proteins form gap junctions, which are intercellular channels that connect adjacent cells and facilitate electrical and metabolic coupling. In patients with lymphedema, variants in GJC2 are predicted to alter gap junction function and disrupt lymphatic flow (Ferrell et al. Am J Human Genet 86:943-948, 2010) resulting in accumulation of lymph in interstitial space. Most causative GJC2 variants are missense variants though several nonsense variants and small and large insertions and deletions have been reported.

Sensitivity of this test is unknown.

This test provides full coverage of all coding exons of the GJC2 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).