SASH1 and Dyschromatosis Universalis Hereditaria

SASH1, a gene implicated in pigmentary skin disorders, has been repeatedly associated with dyschromatosis universalis hereditaria (DUH), an autosomal dominant genodermatosis characterized by a mixture of hyperpigmented and hypopigmented macules. Multiple independent studies have reported heterozygous missense variants in SASH1 in families with DUH, strengthening the gene-disease association (PMID:32174800, PMID:32849825).

Genetic investigations using whole-exome sequencing and segregation analyses across several Chinese families have identified pathogenic variants that co-segregate with the DUH phenotype. For example, in one pivotal report the variant c.1761C>G (p.Ser587Arg) was found to track with disease status in a multi‑generational pedigree (PMID:32174800). Additional case reports have reported other SASH1 missense changes, enhancing the breadth of genetic evidence and supporting a strong genotype‑phenotype correlation (PMID:32849825, PMID:37543808).

The inheritance pattern is predominantly autosomal dominant. Segregation analyses across the reported studies consistently demonstrate that affected family members harbor the mutant allele, with at least 7 additional affected relatives documented in aggregate studies (PMID:37543808). The recurrent identification of heterozygous variants, including the representative c.1761C>G (p.Ser587Arg), underscores the mutational spectrum associated with DUH.

Complementing the genetic data, functional studies have demonstrated that SASH1 mutations disrupt normal melanocyte behavior. In cellular models, mutant SASH1 results in a significant downregulation of SASH1 expression, increased transepithelial migration of melanocytes, and altered TGF-β1 signaling, all of which are consistent with the clinical hyperpigmentation phenotype (PMID:32174800, PMID:23333244).

While DUH exhibits some genetic heterogeneity with occasional involvement of other genes such as ABCB6, the clinical and molecular data specifically supporting SASH1 are robust. The convergence of segregation, replication of the variant across multiple unrelated probands, and concordant functional evidence collectively support a strong clinical validity classification for the SASH1–DUH association.

In summary, the integrated genetic and functional findings establish that SASH1 is strongly associated with dyschromatosis universalis hereditaria. This robust association aids diagnostic decision‑making and has clear implications for commercial genetic testing and future actionable publications.

References

• International journal of biological sciences • 2020 • SASH1 promotes melanin synthesis and migration via suppression of TGF-β1 secretion in melanocytes resulting in pathologic hyperpigmentation PMID:32174800
• Frontiers in genetics • 2020 • Identification of a Novel Mutation in SASH1 Gene in a Chinese Family With Dyschromatosis Universalis Hereditaria and Genotype-Phenotype Correlation Analysis. PMID:32849825
• Medicine • 2023 • Uncovering a new SASH1 mutation associated with dyschromatosis universalis hereditaria using whole‑exome‑sequencing: A case report. PMID:37543808
• Cellular signalling • 2013 • SASH1 regulates melanocyte transepithelial migration through a novel Gαs‑SASH1‑IQGAP1‑E‑Cadherin dependent pathway PMID:23333244

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