Abstract

Background Lymphoedema distichiasis syndrome (LDS) is an autosomal dominant inherited form of lymphoedema, typically presenting with lower limb lymphoedema from puberty and distichiasis from birth. For up to 97% of patients, a coding change in FOXC2 is identifiable. However, a number of case studies identifying structural variants (SVs) outside of the FOXC2 locus have been reported. Methods Using a range of approaches, including genome sequencing, we investigated whether we could identify SVs, which may be impacting FOXC2 in a series of unsolved cases. In silico tools were used to annotate these variants for potential insights into regulatory mechanisms. Results We identified five families with SVs impacting FOXC2. One with a mosaic deletion causing a truncated protein, and four with SVs impacting the non-coding portion of the genome downstream of FOXC2, likely causing dysregulation of the gene. A review of 28 patients in the DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources (DECIPHER) database with 16q24 deletions, including the whole of FOXC2, identified only two reported to have lymphoedema or distichiasis. Conclusion These additional cases bolster the evidence supporting FOXC2 as a monogenic cause of LDS. The fact that these SVs are not detected through panel testing underscores the recommendation for employing genome sequencing or array-comparative genomic hybridisation (CGH) in patients with suspected LDS who lack a genetic diagnosis. Public databases of patients with 16q24 deletions, incorporating FOXC2, but without lymphoedema reported, demand caution when interpreting deletions affecting the entirety of FOXC2. Work is required to explore the role of these putative regulatory elements whose dysregulation may cause this syndrome.