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Identification of a DNA methylation signature for Renpenning syndrome (RENS1), a spliceopathy

European Journal of Human Genetics volume 31, pages 879–886 (2023)Cite this article

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Abstract

The challenges and ambiguities in providing an accurate diagnosis for patients with neurodevelopmental disorders have led researchers to apply epigenetics as a technique to validate the diagnosis provided based on the clinical examination and genetic testing results. Genome-wide DNA methylation analysis has recently been adapted for clinical testing of patients with genetic neurodevelopmental disorders. In this paper, preliminary data demonstrating a DNA methylation signature for Renpenning syndrome (RENS1 – OMIM 309500), which is an X-linked recessive neurodevelopmental disorder caused by variants in polyglutamine-binding protein 1 (PQBP1) is reported. The identified episignature was then utilized to construct a highly sensitive and specific binary classification model. Besides providing evidence for the existence of a DNA methylation episignature for Renpenning syndrome, this study increases the knowledge of the molecular mechanisms related to the disease. Moreover, the availability of more subjects in future may facilitate the establishment of an episignature that can be utilized for diagnosis in a clinical setting and for reclassification of variants of unknown clinical significance.

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Fig. 1: PQBP1 Protein domains.
Fig. 2: Assessing the robustness of the identified episignature.
Fig. 3: 12 rounds of cross-validation.
Fig. 4: Methylation variant pathogenicity (MVP) scores generated by the support vector machine (SVM) classifier.

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Data availability

Some of the datasets used in this study are publicly available and may be obtained from gene expression omnibus (GEO) using the following accession numbers. GEO: GSE116992, GSE66552, GSE74432, GSE97362, GSE116300, GSE95040, GSE 104451, GSE125367, GSE55491, GSE108423, GSE116300, GSE 89353, GSE52588, GSE42861, GSE85210, GSE87571, GSE87648, GSE99863, and GSE35069. These include DNA methylation data from patients with Kabuki syndrome, Sotos syndrome, CHARGE syndrome, immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome, Williams-Beuren syndrome, Chr7q11.23 duplication syndrome, BAFopathies, Down syndrome, a large cohort of unresolved subjects with developmental delays and congenital abnormalities, and also several large cohorts of DNA methylation data from the general population. The rest of the data including the RENS1 samples are not available due to the restrictions of the ethics approval. The variants are publicly available on ClinVar, with accession numbers SCV002525441.1- SCV002525447.1.

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Acknowledgements

We would like to thank the families for their contribution to Greenwood Genetic Center’s (GGC’s) study of X-linked intellectual disabilities. We also appreciate Anna Crockett’s assistance in preparing revisions to the revising of the paper. Dedicated to the memory of Ethan Francis Schwartz, 1996–1998.

Funding

This work was funded in part by the government of Canada through Genome Canada and the Ontario Genomics Institute (OGI-188) awarded to BS, NIH grant HD-026202 to CES, the South Carolina Department of Disabilities and Special Needs, and the Greenwood Genetic Center Foundation.

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Author notes

  1. Charles E. Schwartz

    Present address: Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI, 49503, USA

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Western University, London, ON, N6A 3K7, Canada

    Sadegheh Haghshenas, Aidin Foroutan, Haley McConkey & Bekim Sadikovic

  2. Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, N6A 5W9, Canada

    Sadegheh Haghshenas, Pratibha Bhai, Michael A. Levy, Raissa Relator, Jennifer Kerkhof, Haley McConkey & Bekim Sadikovic

  3. Greenwood Genetic Center, Greenwood, SC, 29646, USA

    Cindy D. Skinner, Raymond C. Caylor, Matthew L. Tedder, Roger E. Stevenson & Charles E. Schwartz

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Contributions

Conceptualization: SH, BS, CES; Data curation: SH, JK; Formal analysis: SH, MAL, RR; Funding acquisition: BS, CES; Investigation: SH, MAL, JK, CDS, RCC; Methodology: SH, MAL, RR; Project administration: HM, BS, CES; Resources: JK, CDS, MLT, RES, BS, CES; Software: SH, MAL, RR; Supervision: BS, CES; Validation: SH, AF, PB; Visualization: SH; Writing-original draft: SH, AF; Writing-review and editing: PB, HM, RES, BS, CES.

Corresponding authors

Correspondence to Bekim Sadikovic or Charles E. Schwartz.

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Competing interests

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential competing interest. CES was previously affiliated with GGC, which provides commercial diagnostic services using EpiSign. This study however, was initiated after his retirement from GGC in collaboration with BS. Some of the genome-wide data was generated at GGC on a research basis at the request of CES. Thus, it is not linked to the commercial diagnostic services at GGC.

Ethics approval

All of the samples and records were de-identified. The study protocol has been approved by the Western University Research Ethics Board (REB 106302), and the IRB of Self Regional Healthcare. Informed consent was obtained by physicians for use of the clinical information of the described patients.

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Haghshenas, S., Foroutan, A., Bhai, P. et al. Identification of a DNA methylation signature for Renpenning syndrome (RENS1), a spliceopathy. Eur J Hum Genet 31, 879–886 (2023). https://doi.org/10.1038/s41431-023-01313-z

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