SHH – Triphalangeal Thumb-Polysyndactyly Syndrome

Triphalangeal thumb-polysyndactyly syndrome (TPT-PS) is an autosomal dominant limb malformation characterized by a thumb with three phalanges and preaxial polydactyly. Two unrelated families, one Dutch and one large Polish pedigree, carry the same non-coding point mutation in the pre-ZRS regulatory element of SHH (NC_000007.14:g.156792782C>G), which segregates with disease in the Polish kindred (PMID:35821352). This variant was absent in controls and represents a recurrent gain-of-function regulatory alteration upstream of SHH. Routine sequencing of the pZRS region is recommended in TPT-PS diagnostics.

Functional circular chromatin conformation capture (4C-seq) performed on patient fibroblasts demonstrated increased interactions across the SHH limb regulatory domain (SHH-LMBR1 TAD) relative to controls, supporting a mechanism of ectopic anterior SHH activation in limb buds (PMID:35821352). No conflicting reports have been published, and the concordant genetic and epigenomic data establish a Limited clinical validity for SHH in TPT-PS pending further segregation and additional pedigrees. Key takeaway: pZRS sequencing is clinically useful for AD TPT-PS diagnosis.

References

• Molecular genetics and genomics : MGG • 2022 • The pZRS non-coding regulatory mutation resulting in triphalangeal thumb-polysyndactyly syndrome changes the pattern of local interactions. PMID:35821352

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