SOX18 – Hypotrichosis-Lymphedema-Telangiectasia Syndrome

This summary documents the association between SOX18 and hypotrichosis-lymphedema-telangiectasia syndrome. Multiple independent studies provide robust evidence for a strong gene‑disease association (PMID:26148450, PMID:33851505). In several reports, both de novo and familial occurrences have been noted with the identification of heterozygous mutations in SOX18. This body of evidence supports a ClinGen category of Strong given the number of independent probands and the concordance of experimental data with clinical findings.

Genetic Evidence: The disease follows an autosomal dominant inheritance pattern. Multiple case reports describe affected individuals harboring heterozygous mutations, including a clearly defined variant, c.481C>T (p.Gln161Ter) (PMID:26148450). Additional cases have shown segregation of the phenotype in affected relatives, with supportive evidence from both single‐patient reports and multi‑patient studies that report a diverse spectrum of variants (nonsense, frameshift) leading to haploinsufficiency.

Functional / Experimental Evidence: Functional studies in murine models and in vitro cell systems have demonstrated that SOX18 mutations disrupt its transcriptional activity in endothelial cells and hair follicles (PMID:10742113, PMID:11554755). Such assays reveal impaired activation of downstream targets, consistent with defects in vascular development, lymphangiogenesis, and hair formation. The experimental data further support the pathogenic mechanism of loss‑of‑function, in line with the clinical phenotype.

Segregation and Variant Spectrum: In addition to the de novo events, familial studies have identified segregation of the pathogenic variant in multiple affected individuals, with additional affected relatives reported across different studies. A broad variant spectrum has been observed, including truncating mutations such as c.481C>T (p.Gln161Ter) and others affecting the transactivation domain. These observations bolster the genetic evidence for SOX18 involvement in this syndrome.

Clinical Integration: Integrating both the genetic and functional data, the association of SOX18 with hypotrichosis‑lymphedema‑telangiectasia syndrome is well supported by independent case reports, segregation analyses, and in vivo experimental studies. Additional evidence beyond the ClinGen cap exists, but the current data satisfy the criteria for a strong association.

Key Take‑home: Genetic testing for SOX18 mutations is highly recommended in patients presenting with congenital hypotrichosis, lymphedema, and telangiectasia given its clear clinical utility.

References

• The Canadian journal of cardiology • 2016 • Aortic Dilatation Associated With a De Novo Mutation in the SOX18 Gene: Expanding the Clinical Spectrum of Hypotrichosis-Lymphedema-Telangiectasia Syndro PMID:26148450
• Molecular and cellular probes • 2016 • A novel SOX18 mutation uncovered in Jordanian patient with hypotrichosis-lymphedema-telangiectasia syndrome by Whole Exome Sequencing PMID:26631803
• American journal of medical genetics. Part A • 2018 • A novel autosomal dominant mutation in SOX18 resulting in a fatal case of hypotrichosis-lymphedema-telangiectasia syndrome PMID:30549413
• American journal of medical genetics. Part A • 2021 • Hypotrichosis-lymphedema-telangiectasia syndrome: Report of ileal atresia associated with a SOX18 de novo pathogenic variant and review of the phenotypic spectrum PMID:33851505
• Nature genetics • 2000 • Mutations in Sox18 underlie cardiovascular and hair follicle defects in ragged mice PMID:10742113

Evidence Based Scoring (AI generated)