The pZRS non-coding regulatory mutation resulting in triphalangeal thumb–polysyndactyly syndrome changes the pattern of local interactions

Jacob W.P. Potuijt, Anna Sowinska-Seidler*, Ewelina Bukowska-Olech, Picard Nguyen, Aleksander Jankowski, Frank Magielsen, Karolina Matuszewska, Christianne A. van Nieuwenhoven, Robert Jan H. Galjaard, Annelies de Klein, Aleksander Jamsheer

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Herein, we report on a large Polish family presenting with a classical triphalangeal thumb–polysyndactyly syndrome (TPT-PS). This rare congenital limb anomaly is generally caused by microduplications encompassing the Sonic Hedgehog (SHH) limb enhancer, termed the zone of polarizing activity (ZPA) regulatory sequence (ZRS). Recently, a pathogenic variant in the pre-ZRS (pZRS), a conserved sequence located near the ZRS, has been described in a TPT-PS Dutch family. We performed targeted ZRS sequencing, array comparative genomic hybridization, and whole-exome sequencing. Next, we sequenced the recently described pZRS region. Finally, we performed a circular chromatin conformation capture-sequencing (4C-seq) assay on skin fibroblasts of one affected family member and control samples to examine potential alterations in the SHH regulatory domain and functionally characterize the identified variant. We found that all affected individuals shared a recently identified pathogenic point mutation in the pZRS region: NC_000007.14:g.156792782C>G (GRCh38/hg38), which is the same as in the Dutch family. The results of 4C-seq experiments revealed increased interactions within the whole SHH regulatory domain (SHH-LMBR1 TAD) in the patient compared to controls. Our study expands the number of TPT-PS families carrying a pathogenic alteration of the pZRS and underlines the importance of routine pZRS sequencing in the genetic diagnostics of patients with TPT-PS or similar phenotypes. The pathogenic mutation causative for TPT-PS in our patient gave rise to increased interactions within the SHH regulatory domain in yet unknown mechanism.

Original languageEnglish
Pages (from-to)1343-1352
Number of pages10
JournalMolecular Genetics and Genomics
Volume297
Issue number5
DOIs
Publication statusPublished - Sept 2022

Bibliographical note

Funding Information:
A.S.-S. was supported by the Polish National Science Centre (grant: UMO-2016/21/D/NZ5/00064). A. Jankowski was supported by the Polish National Agency for Academic Exchange (Polish Returns 2019). A. Jamsheer was supported by the Polish National Science Centre (grant: UMO-2016/22/E/NZ5/00270).

Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

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