ADAMTS3 – Hennekam lymphangiectasia-lymphedema syndrome

ADAMTS3 has been implicated in Hennekam lymphangiectasia-lymphedema syndrome (HKLLS3) as an autosomal recessive disorder. A single affected individual was found to carry a homozygous nonsense variant, c.280C>T (p.Arg94Ter), which is predicted to truncate the protease domain and abolish VEGF-C activation by ADAMTS3 (PMID:30450763). No additional segregation beyond this proband has been reported to date. Based on ClinGen criteria, this constitutes Limited clinical validity for the ADAMTS3–HKLLS3 association, as only one family has been described without extended segregation data.

In silico pathogenicity analyses have nominated dozens of high-risk nonsynonymous SNPs in ADAMTS3 that are predicted to destabilize its structure, including variants in all major catalytic and ancillary domains, supporting a loss-of-function mechanism (PMID:37322437). However, these predictions lack experimental confirmation in patient cells or animal models. No conflicting evidence has emerged. Further unrelated cases with biallelic ADAMTS3 variants and functional rescue studies are required to bolster the gene–disease association. Key take-home: Biallelic loss-of-function ADAMTS3 variants are a putative cause of Hennekam syndrome, though current evidence remains Limited.

References

• American journal of medical genetics. Part A • 2018 • An additional case of Hennekam lymphangiectasia-lymphedema syndrome caused by loss-of-function mutation in ADAMTS3. PMID:30450763
• BMC bioinformatics • 2023 • In-silico assessment of high-risk non-synonymous SNPs in ADAMTS3 gene associated with Hennekam syndrome and their impact on protein stability and function. PMID:37322437

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