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.