It all begins with the phenotype

The recent paper by Xu et al. investigated a Chinese fourgeneration family with a polydactylous limb anomaly.1 Affected family members shared a sequence variant in an enhancer of Sonic Hedgehog (SHH), a gene essential for embryonic limb patterning. The reported variant (446T>A) in this well-known enhancer, termed the ZRS, has not been described in literature before. Additionally, the paper extensively evaluated the pathogenic effect of the variant with a combined approach, using CRISPR/Cas9 targeted transgenic mice models, electrophorectic mobility shift assays (EMSA), chromatin immunoprecipitation (ChIP) assays, and luciferase reporter assays. As the most important conclusion, the authors claim that this is the first case of a preaxial polydactyly type 1 (PPD I) family associated with a variant in the ZRS and therefore adds PPD I to the spectrum of ZRS-associated phenotypes. However, after reviewing the provided images and descriptions, we believe that the phenotypes of the affected members of this family should not be classified as preaxial polydactyly type I (PPD I), but as triphalangeal thumb (TPT), a limb anomaly commonly associated with variants in the ZRS. We will substantiate our argument with three explanations on the observations made in this paper:

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