Abstract
Purpose
HNRNPU haploinsufficiency is associated with developmental and epileptic encephalopathy
54. This neurodevelopmental disorder is characterized by developmental delay, intellectual
disability, speech impairment, and early-onset epilepsy. We performed genome-wide
DNA methylation (DNAm) analysis in a cohort of individuals to develop a diagnostic
biomarker and gain functional insights into the molecular pathophysiology of HNRNPU-related disorder.
Methods
DNAm profiles of individuals carrying pathogenic HNRNPU variants, identified through an international multicenter collaboration, were assessed
using Infinium Methylation EPIC arrays. Statistical and functional correlation analyses
were performed comparing the HNRNPU cohort with 56 previously reported DNAm episignatures.
Results
A robust and reproducible DNAm episignature and global DNAm profile were identified.
Correlation analysis identified partial overlap and similarity of the global HNRNPU DNAm profile to several other rare disorders.
Conclusion
This study demonstrates new evidence of a specific and sensitive DNAm episignature
associated with pathogenic heterozygous HNRNPU variants, establishing its utility as a clinical biomarker for the expansion of the
EpiSign diagnostic test.
Keywords
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References
- Heterozygous HNRNPU variants cause early onset epilepsy and severe intellectual disability.Hum Genet. 2017; 136: 821-834https://doi.org/10.1007/s00439-017-1795-6
- Expanding the phenotype of HNRNPU-related neurodevelopmental disorder with emphasis on seizure phenotype and review of literature.Am J Med Genet A. 2022; 188: 1497-1514https://doi.org/10.1002/ajmg.a.62677
- Molecular basis for the specific and multivariant recognitions of RNA substrates by human hnRNP A2/B1.Nat Commun. 2018; 9: 420https://doi.org/10.1038/s41467-017-02770-z
- HnRNP Q Has a suppressive role in the translation of mouse Cryptochrome1.PLoS One. 2016; 11e0159018https://doi.org/10.1371/journal.pone.0159018
- The hnRNP family: insights into their role in health and disease.Hum Genet. 2016; 135: 851-867https://doi.org/10.1007/s00439-016-1683-5
- Heterogeneous nuclear ribonucleoprotein U (HNRNPU) safeguards the developing mouse cortex.Nat Commun. 2022; 13: 4209https://doi.org/10.1038/s41467-022-31752-z
- Analysis of the nucleocytoplasmic shuttling RNA-binding protein HNRNPU using optimized HITS-CLIP method.PLoS One. 2020; 15e0231450https://doi.org/10.1371/journal.pone.0231450
- The role of nuclear matrix protein HNRNPU in maintaining the architecture of 3D genome.Semin Cell Dev Biol. 2019; 90: 161-167https://doi.org/10.1016/j.semcdb.2018.07.006
- The Mendelian disorders of the epigenetic machinery.Genome Res. 2015; 25: 1473-1481https://doi.org/10.1101/gr.190629.115
- Mendelian disorders of the epigenetic machinery: tipping the balance of chromatin states.Annu Rev Genomics Hum Genet. 2014; 15: 269-293https://doi.org/10.1146/annurev-genom-090613-094245
- DNA methylation signatures in Mendelian developmental disorders as a diagnostic bridge between genotype and phenotype.Epigenomics. 2019; 11: 563-575https://doi.org/10.2217/epi-2018-0192
- Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders.HGG Adv. 2022; 3100075https://doi.org/10.1016/j.xhgg.2021.100075
- Identification of a DNA methylation episignature in the 22q11.2 deletion syndrome.Int J Mol Sci. 2021; 22: 8611https://doi.org/10.3390/ijms22168611
- DNA methylation episignatures in neurodevelopmental disorders associated with large structural copy number variants: clinical implications.Int J Mol Sci. 2022; 23: 7862https://doi.org/10.3390/ijms23147862
- DNA methylation episignatures: insight into copy number variation.Epigenomics. 2022; 14: 1373-1388https://doi.org/10.2217/epi-2022-0287
- Genomic DNA methylation signatures enable concurrent diagnosis and clinical genetic variant classification in neurodevelopmental syndromes.Am J Hum Genet. 2018; 102: 156-174https://doi.org/10.1016/j.ajhg.2017.12.008
Balasubramanian M. HNRNPU-related neurodevelopmental disorder. In: Adam MP, Everman DB, Mirzaa GM, et al, editors. GeneReviews(®). University of Washington; 1993-2023.
- Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU.Hum Genet. 2017; 136: 463-479https://doi.org/10.1007/s00439-017-1772-0
- Clinical findings of 21 previously unreported probands with HNRNPU-related syndrome and comprehensive literature review.Am J Med Genet A. 2020; 182: 1637-1654https://doi.org/10.1002/ajmg.a.61599
- Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Genet Med. 2015; 17: 405-424https://doi.org/10.1038/gim.2015.30
- Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen).Genet Med. 2020; 22: 245-257https://doi.org/10.1038/s41436-019-0686-8
- SIFT missense predictions for genomes.Nat Protoc. 2016; 11: 1-9https://doi.org/10.1038/nprot.2015.123
- Pathogenicity and functional impact of non-frameshifting insertion/deletion variation in the human genome.PLoS Comput Biol. 2019; 15e1007112https://doi.org/10.1371/journal.pcbi.1007112
- MutationTaster2021.Nucleic Acids Res. 2021; 49: W446-W451https://doi.org/10.1093/nar/gkab266
- Episignature mapping of TRIP12 provides functional insight into Clark–Baraitser syndrome.Int J Mol Sci. 2022; 2313664https://doi.org/10.3390/ijms232213664
- Functional correlation of genome-wide DNA methylation profiles in genetic neurodevelopmental disorders.Hum Mutat. 2022; 43: 1609-1628https://doi.org/10.1002/humu.24446
- Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays.Bioinformatics. 2014; 30: 1363-1369https://doi.org/10.1093/bioinformatics/btu049
- MatchIt: nonparametric preprocessing for parametric causal inference.J Stat Softw. 2011; 42: 1-28https://doi.org/10.18637/jss.v042.i08
- limma powers differential expression analyses for RNA-sequencing and microarray studies.Nucleic Acids Res. 2015; 43: e47https://doi.org/10.1093/nar/gkv007
- DNA methylation arrays as surrogate measures of cell mixture distribution.BMC Bioinformatics. 2012; 13: 86https://doi.org/10.1186/1471-2105-13-86
- De novo identification of differentially methylated regions in the human genome.Epigenetics Chromatin. 2015; 8: 6https://doi.org/10.1186/1756-8935-8-6
- circlize implements and enhances circular visualization in R.Bioinformatics. 2014; 30: 2811-2812https://doi.org/10.1093/bioinformatics/btu393
- Annotatr: genomic regions in context.Bioinformatics. 2017; 33: 2381-2383https://doi.org/10.1093/bioinformatics/btx183
- The human genome browser at UCSC.Genome Res. 2002; 12: 996-1006https://doi.org/10.1101/gr.229102
- Diagnostic utility of genome-wide DNA methylation testing in genetically unsolved individuals with suspected hereditary conditions.Am J Hum Genet. 2019; 104: 685-700https://doi.org/10.1016/j.ajhg.2019.03.008
- Gene domain-specific DNA methylation episignatures highlight distinct molecular entities of ADNP syndrome.Clin Epigenet. 2019; 11: 64https://doi.org/10.1186/s13148-019-0658-5
- Clinical epigenomics: genome-wide DNA methylation analysis for the diagnosis of Mendelian disorders.Genet Med. 2021; 23: 1065-1074https://doi.org/10.1038/s41436-020-01096-4
- Toward clinical and molecular understanding of pathogenic variants in the ZBTB18 gene.Mol Genet Genom Med. 2018; 6: 393-400https://doi.org/10.1002/mgg3.387
- Four patients with speech delay, seizures and variable corpus callosum thickness sharing a 0.440-Mb deletion in region 1q44 containing the HNRPU gene.Eur J Med Genet. 2010; 53: 179-185https://doi.org/10.1016/j.ejmg.2010.04.001
- Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios.Genet Med. 2015; 17: 774-781https://doi.org/10.1038/gim.2014.191
- Detection of a DNA methylation signature for the intellectual developmental disorder, X-linked, syndromic, Armfield type.Int J Mol Sci. 2021; 22: 1111https://doi.org/10.3390/ijms22031111
- HNRNPR variants that impair homeobox gene expression drive developmental disorders in humans.Am J Hum Genet. 2019; 104: 1040-1059https://doi.org/10.1016/j.ajhg.2019.03.024
- Mammalian SWI/SNF chromatin remodeling complexes: emerging mechanisms and therapeutic strategies.Trends Genet. 2020; 36: 936-950https://doi.org/10.1016/j.tig.2020.07.011
- The SWI/SNF subunit BRG1 affects alternative splicing by changing RNA binding factor interactions with nascent RNA.Mol Genet Genomics. 2022; 297: 463-484https://doi.org/10.1007/s00438-022-01863-9
- The diverse roles of DNA methylation in mammalian development and disease.Nat Rev Mol Cell Biol. 2019; 20: 590-607https://doi.org/10.1038/s41580-019-0159-6
- DNA methylation signature for JARID2-neurodevelopmental syndrome.Int J Mol Sci. 2022; 23: 8001https://doi.org/10.3390/ijms23148001
Article info
Publication history
Published online: April 27, 2023
Accepted:
April 24,
2023
Received in revised form:
April 24,
2023
Received:
January 19,
2023
Footnotes
The Article Publishing Charge (APC) for this article was paid by Peter Henneman.
Kathleen Rooney and Liselot van der Laan contributed equally to this work.
Bekim Sadikovic, Mieke M. van Haelst, and Peter Henneman are senior authors contributed equally to this work.
Identification
Copyright
© 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.
