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TP63 – Split Hand-Foot Malformation

Heterozygous mutations in TP63 underlie autosomal dominant non-syndromic split hand-foot malformation (SHFM4). A case series reported a single proband with SHFM carrying the c.779C>A (p.Ala260Glu) variant, supporting a direct gene–disease link (1 proband (PMID:17224651)). Functional assays demonstrate that p63 missense mutations abolish DNA-binding and disrupt oligomerization, acting via a dominant-negative mechanism concordant with human limb malformation (PMID:10535733).

References

  • Cell cycle (Georgetown, Tex.) • 2007 • p63-associated disorders. PMID:17224651
  • Cell • 1999 • Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome. PMID:10535733

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Case reports of heterozygous TP63 variant in non-syndromic SHFM (1 proband (PMID:17224651)).

Genetic Evidence

Limited

Single proband with c.779C>A (p.Ala260Glu) supports an association but lacks broader familial segregation.

Functional Evidence

Moderate

In vitro studies show dominant-negative effects of p63 mutants impairing DNA binding and oligomerization (PMID:10535733).