Novel biallelic splicing and deletion variants of ADAMTS3 found in adult patients with Hennekam lymphangiectasia-lymphedema syndrome 3

Background ADAM metallopeptidase with thrombospondin type 1 motif 3 ( ADAMTS3 ) is one of the causative genes for the Hennekam lymphangiectasia-lymphedema syndrome (HKLLS), an autosomal recessive genetic disorder. Here, we reported novel biallelic variants of ADAMTS3 in adult patients affected by HKLLS. Methods The variants were identified via whole-exome sequencing and SNP microarray and confirmed via Sanger sequencing. A minigene-based splicing assay assessed variant effects on splicing. A Pro-vascular endothelial growth factor C (Pro-VEGFC) processing assay evaluated mutant ADAMTS3 function. Results A novel heterozygous deletion of a 308-kb region spanning exons 1–3 of ADAMTS3 was detected in the two affected sisters with HKLLS and their mother. Additionally, a novel heterozygous variant (NM_014243.3:c.1352+5G>T: IVS9+5G>T) located near the splice junction of exon 9 in another allele was found in the two affected sisters. Minigene-based splicing assays revealed splicing abnormalities caused by the variant (IVS9+5G>T). The major splicing variant encoded an in-frame truncated protein. The Pro-VEGFC assay showed this truncated protein failed to mature VEGFC, essential for lymphangiogenesis. Conclusion This is the first report of a pathogenic splicing variant in ADAMTS3 , leading to HKLLS. ADAMTS3 should also be investigated in neonatal oedema. Our findings will broaden the variant spectrum and contribute to the understanding of the pathogenesis of HKLLS.