p63 gene mutations in EEC syndrome, limb-mammary syndrome, and isolated split hand-split foot malformation suggest a genotype-phenotype correlation

p63 mutations have been associated with EEC syndrome (ectrodactyly, ectoder mal dysplasia, and cleft lip/palate), as well as with nonsyndromic split ha nd-split foot malformation (SHFM). We performed p63 mutation analysis in a sample of 43 individuals and families affected with EEC syndrome, in 35 ind ividuals affected with SHFM, and in three families with the EEC-like condit ion limb-mammary syndrome (LMS), which is characterized by ectrodactyly, cl eft palate, and mammary-gland abnormalities. The results differed for these three conditions. p63 gene mutations were detected in almost all (40/43) i ndividuals affected with EEC syndrome. Apart from a frameshift mutation in exon 13, all other EEC mutations were missense, predominantly involving cod ons 204, 227, 279, 280, and 304. In contrast, p63 mutations were detected i n only a small proportion (4/35) of patients with isolated SHFM. p63 mutati ons in SHFM included three novel mutations: a missense mutation (K193E), a nonsense mutation (Q634X), and a mutation in the 3' splice site for exon 5. The fourth SHFM mutation (R280H) in this series was also found in a patien t with classical EEC syndrome, suggesting partial overlap between the EEC a nd SHFM mutational spectra. The original family with LMS (van Bokhoven et a l. 1999) had no detectable p63 mutation, although it clearly localizes to t he p63 locus in 3q27. In two other small kindreds affected with LMS, frames hift mutations were detected in exons 13 and 14, respectively. The combined data show that p63 is the major gene for EEC syndrome, and that it makes a modest contribution to SHFM. There appears to be a genotype-phenotype corr elation, in that there is a specific pattern of missense mutations in EEC s yndrome that are not generally found in SHFM or LMS.