Germline intergenic duplications at Xq26.1 underlie Bazex–Dupré–Christol basal cell carcinoma susceptibility syndrome

Background Bazex–Dupré–Christol syndrome (BDCS; MIM301845) is a rare X‐linked dominant genodermatosis characterized by follicular atrophoderma, congenital hypotrichosis and multiple basal cell carcinomas (BCCs). Previous studies have linked BDCS to an 11·4‐Mb interval on chromosome Xq25‐q27.1. Howev...

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Published in:British journal of dermatology (1951) 2022-12, Vol.187 (6), p.948-961
Main Authors: Liu, Yanshan, Banka, Siddharth, Huang, Yingzhi, Hardman‐Smart, Jonathan, Pye, Derek, Torrelo, Antonio, Beaman, Glenda M., Kazanietz, Marcelo G., Baker, Martin J., Ferrazzano, Carlo, Shi, Chenfu, Orozco, Gisela, Eyre, Stephen, Geel, Michel, Bygum, Anette, Fischer, Judith, Miedzybrodzka, Zosia, Abuzahra, Faris, Rübben, Albert, Cuvertino, Sara, Ellingford, Jamie M., Smith, Miriam J., Evans, D. Gareth, Weppner‐Parren, Lizelotte J.M.T., Steensel, Maurice A.M., Chaudhary, Iskander H., Mangham, D. Chas, Lear, John T., Paus, Ralf, Frank, Jorge, Newman, William G., Zhang, Xue
Format: Article
Language:English
Subjects:
Alleles
Basal cell carcinoma
Carcinoma
Carcinoma, Basal Cell - pathology
Chromosomes
Comparative Genomic Hybridization
Copy number
DNA Copy Number Variations - genetics
Enhancers
Fibroblasts
Follicles
Gene frequency
Genetic screening
Genodermatosis
Germ Cells - pathology
Hair
Humans
Hybridization
Hypotrichosis - genetics
Hypotrichosis - pathology
Immunofluorescence
Microfilament Proteins
Molecular modelling
Patients
Polymerase chain reaction
Population genetics
Regulatory sequences
Skin cancer
Stem cells
Therapeutic applications
Therapeutic targets
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Summary:Background Bazex–Dupré–Christol syndrome (BDCS; MIM301845) is a rare X‐linked dominant genodermatosis characterized by follicular atrophoderma, congenital hypotrichosis and multiple basal cell carcinomas (BCCs). Previous studies have linked BDCS to an 11·4‐Mb interval on chromosome Xq25‐q27.1. However, the genetic mechanism of BDCS remains an open question. Objectives To investigate the genetic aetiology and molecular mechanisms underlying BDCS. Methods We ascertained multiple individuals from eight unrelated families affected with BDCS (F1–F8). Whole‐exome (F1 and F2) and genome sequencing (F3) were performed to identify putative disease‐causing variants within the linkage region. Array comparative genomic hybridization and quantitative polymerase chain reaction (PCR) were used to explore copy number variations, followed by long‐range gap PCR and Sanger sequencing to amplify the duplication junctions and to define the head–tail junctions. Hi‐C was performed on dermal fibroblasts from two affected individuals with BDCS and one control. Public datasets and tools were used to identify regulatory elements and transcription factor binding sites within the minimal duplicated region. Immunofluorescence was performed in hair follicles, BCCs and trichoepitheliomas from patients with BDCS and sporadic BCCs. The ACTRT1 variant c.547dup (p.Met183Asnfs*17), previously proposed to cause BDCS, was evaluated with t allele frequency calculator. Results In eight families with BDCS, we identified overlapping 18–135‐kb duplications (six inherited and two de novo) at Xq26.1, flanked by ARHGAP36 and IGSF1. Hi‐C showed that the duplications did not affect the topologically associated domain, but may alter the interactions between flanking genes and putative enhancers located in the minimal duplicated region. We detected ARHGAP36 expression near the control hair follicular stem cell compartment, and found increased ARHGAP36 levels in hair follicles in telogen, in BCCs and in trichoepitheliomas from patients with BDCS. ARHGAP36 was also detected in sporadic BCCs from individuals without BDCS. Our modelling showed the predicted maximum tolerated minor allele frequency of ACTRT1 variants in control populations to be orders of magnitude higher than expected for a high‐penetrant ultra‐rare disorder, suggesting loss of function of ACTRT1 variants to be an unlikely cause for BDCS. Conclusions Noncoding Xq26.1 duplications cause BDCS. The BDCS duplications most likely lead to dysregulat
ISSN:0007-0963
1365-2133
DOI:10.1111/bjd.21842