Novel GJC2 and OBSCN variants co-segregating in a Chinese primary lymphedema pedigree

Abstract Background Primary lymphedema (PL) is a genetically heterogeneous disorder of the lymphatic system. Despite the identification of numerous monogenic causes, the genetic etiology of many familial cases remains elusive, often exhibiting marked phenotypic variability that suggests non-Mendelian or complex inheritance patterns. Results We investigated a four-generation Chinese pedigree presenting with autosomal dominant generalized lymphedema affecting all four limbs, with marked phenotypic variability. Whole-exome sequencing in eight key family members, followed by Sanger sequencing in all 26 available relatives, identified two novel heterozygous missense variants that co-segregated with the disease: GJC2 c.287G > T (p.Gly96Val) and OBSCN c.22393T > A (p.Phe7465Ile). The GJC2 variant affects the second transmembrane domain of connexin 47, whereas the OBSCN variant lies in immunoglobulin-like domain 55 of obscurin, a large cytoskeletal signaling protein not previously implicated in lymphedema. In silico structural modeling predicted that both variants alter local packing and compromise protein stability. Haplotype analysis revealed that these two genes, located approximately 210 kb apart on chromosome 1q42.13, reside on a shared haplotype block with linkage disequilibrium, consistent with co-inheritance as a single pathogenic haplotype. Conclusions To our knowledge, this is the first report linking OBSCN to human lymphedema. We propose a synergistic oligogenic model in which GJC2 disruption impairs lymphatic pumping coordination, while the co-segregating OBSCN variant compromises cytoskeletal integrity and RhoA signaling in lymphatic endothelial cells; together these effects could explain the early-onset, severe phenotype observed in this family. These findings expand the genetic spectrum of PL and highlight the importance of considering closely linked modifier genes in complex inheritance patterns.