Abstract
The GJA4 gene encodes connexin 37 or Gap junction protein alpha-4. Gap junction proteins are required for lymphatic valvulogenesis. It is known that homozygous knockout of the Gja4 gene in mice leads to lymphatic system dysfunction and absent venous valves. In this report, we identify for the first time a homozygous nonsense variant in the GJA4 gene, c.97delC (transcript ID NM_002060.3) or p.Arg33Alafs*98, or chr1:g.34794309delC (GRCh38 format) in a human fetus with increased nuchal fold thickness and abnormal fetal ductus venosus termination. Asymptomatic parents were carriers of the same variant. Additionally, a search of the literature showed that this specific variant in the GJA4 gene has not been previously documented as a cause of human fetal disease. A STRING (Search Tool for Retrieval of Interacting Genes/Proteins) database analysis showed close interactions between the GJA4 gene and other genes involved in the causation of hereditary lymphedema: ADAMTS3, CCBE1, FAT4, FLT4, FOXC2, GATA2, GJA1, GJC2, KIF11, MDFIC, PIEZO1, PIK3CA, PTPN14, RASA1, SOX18, and VEGFC. However, STRING database analysis also showed no interaction of the GJA4 gene with genes in the rasopathy pathway, which can also be causative of increased fetal nuchal translucency, namely BRAF, CBL, HRAS, KRAS, LZTR1, MAP2K1, MAP2K2, MAP3K8, MAPK1, MRAS, NF1, NRAS, PPPC1B, PTPN11, RAF1, RASA2, RIT1, RRAS, SHOC2, SOS2, and SPRED1. Thus, we describe a novel gene-human fetal phenotype association.