Comprehensive EHMT1 variants analysis broadens genotype-phenotype associations and molecular mechanisms in Kleefstra syndrome

Rots D, Bouman A, Yamada A, Levy M, Dingemans AJ, de Vries BB, Ruiterkamp-Versteeg M, de Leeuw N, Ockeloen CW, Pfundt R, de Boer E, Kummeling J, van Bon B, van Bokhoven H, Kasri NN, Venselaar H, Alders M, Kerkhof J, McConkey H, Kuechler A, Elffers B, van Beeck Calkoen R, Hofman S, Smith A, Valenzuela MI, Srivastava S, Frazier Z, Maystadt I, Piscopo C, Merla G, Balasubramanian M, Santen GW, Metcalfe K, Park SM, Pasquier L, Banka S, Donnai D, Weisberg D, Strobl-Wildemann G, Wagemans A, Vreeburg M, Baralle D, Foulds N, Scurr I, Brunetti-Pierri N, van Hagen JM, Bijlsma EK, Hakonen AH, Courage C, Genevieve D, Pinson L, Forzano F, Deshpande C, Kluskens ML, Welling L, Plomp AS, Vanhoutte EK, Kalsner L, Hol JA, Putoux A, Lazier J, Vasudevan P, Ames E, O'Shea J, Lederer D, Fleischer J, O'Connor M, Pauly M, Vasileiou G, Reis A, Kiraly-Borri C, Bouman A, Barnett C, Nezarati M, Borch L, Beunders G, Özcan K, Miot S, Volker-Touw CM, van Gassen KL, Cappuccio G, Janssens K, Mor N, Shomer I, Dominissini D, Tedder ML, Muir AM, Sadikovic B, Brunner HG, Vissers LE, Shinkai Y, Kleefstra T (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Book Volume: 111

Pages Range: 1605-1625

Journal Issue: 8

DOI: 10.1016/j.ajhg.2024.06.008

Abstract

The shift to a genotype-first approach in genetic diagnostics has revolutionized our understanding of neurodevelopmental disorders, expanding both their molecular and phenotypic spectra. Kleefstra syndrome (KLEFS1) is caused by EHMT1 haploinsufficiency and exhibits broad clinical manifestations. EHMT1 encodes euchromatic histone methyltransferase-1—a pivotal component of the epigenetic machinery. We have recruited 209 individuals with a rare EHMT1 variant and performed comprehensive molecular in silico and in vitro testing alongside DNA methylation (DNAm) signature analysis for the identified variants. We (re)classified the variants as likely pathogenic/pathogenic (molecularly confirming Kleefstra syndrome) in 191 individuals. We provide an updated and broader clinical and molecular spectrum of Kleefstra syndrome, including individuals with normal intelligence and familial occurrence. Analysis of the EHMT1 variants reveals a broad range of molecular effects and their associated phenotypes, including distinct genotype-phenotype associations. Notably, we showed that disruption of the “reader” function of the ankyrin repeat domain by a protein altering variant (PAV) results in a KLEFS1-specific DNAm signature and milder phenotype, while disruption of only “writer” methyltransferase activity of the SET domain does not result in KLEFS1 DNAm signature or typical KLEFS1 phenotype. Similarly, N-terminal truncating variants result in a mild phenotype without the DNAm signature. We demonstrate how comprehensive variant analysis can provide insights into pathogenesis of the disorder and DNAm signature. In summary, this study presents a comprehensive overview of KLEFS1 and EHMT1, revealing its broader spectrum and deepening our understanding of its molecular mechanisms, thereby informing accurate variant interpretation, counseling, and clinical management.

Authors with CRIS profile

Involved external institutions

University Hospital Southampton NHS United Kingdom (GB) University Hospitals Bristol NHS Foundation Trust United Kingdom (GB) Università degli Studi di Napoli Federico II Italy (IT) Vrije Universiteit Amsterdam (VU) / University Amsterdam Netherlands (NL) University Hospitals of Leicester NHS Trust United Kingdom (GB) C. S. Mott Children's Hospital United States (USA) (US) King Edward Memorial Hospital Australia (AU) Erasmus University Medical Center (MC) Netherlands (NL) Women’s and Children’s Hospital Australia (AU) North York General Hospital (NYGH) Canada (CA) University of Toronto Canada (CA) Radboud University Nijmegen Medical Centre / Radboudumc of voluit Radboud Universitair Medisch Centrum (UMC) Netherlands (NL) Leiden University Medical Center Netherlands (NL) Cambridge University Hospitals United Kingdom (GB) Health Innovation Manchester United Kingdom (GB) Hospices Civils de Lyon (CHU) France (FR) Children's Hospital of Eastern Ontario (CHEO) / Centre hospitalier pour enfants de l'est de l'Ontario Canada (CA) Southern Illinois University United States (USA) (US) University Medical Center Groningen (UMCG) / Universitair Medisch Centrum Groningen Netherlands (NL) BOBATH THERAPISTS ASSOCIATION Turkey (TR) Hospital Network Antwerp / Ziekenhuis Netwerk Antwerpen (ZNA) Belgium (BE) Chaim Sheba Medical Center at Tel HaShomer / המרכז הרפואי עש חיים שיבא – תל השומר‎‎ Israel (IL) Greenwood Genetic Center United States (USA) (US) Riken Institute of Physical and Chemical Research / 理化学研究所 Japan (JP) London Health Sciences Centre Canada (CA) University of Amsterdam Netherlands (NL) Universitätsklinikum Essen Germany (DE) Cordaan Netherlands (NL) Evean Netherlands (NL) Vall d'Hebron University Hospital / Hospital Universitari Vall d'Hebron Spain (ES) Boston Children's Hospital United States (USA) (US) Veterans Affairs Healthcare System Boston and Harvard Medical School United States (USA) (US) L'Azienda Ospedaliera di Rilievo Nazionale Antonio Cardarelli Italy (IT) University of Sheffield United Kingdom (GB) Centre hospitalier universitaire de Rennes / CHU Rennes France (FR) Maastricht University Netherlands (NL) Helsingin yliopisto / University of Helsinki Finland (FI) University of Montpellier / Université Montpellier France (FR) Centre Hospitalier Universitaire de Montpellier (CHU/CHRU MTP) France (FR) Guy's and St Thomas' (NHS Foundation Trust) United Kingdom (GB) Prinsenstichting Netherlands (NL) University of Connecticut United States (USA) (US) University Medical Centre Utrecht (UMC Utrecht) Netherlands (NL) GeneDX United States (USA) (US)

How to cite

APA:

Rots, D., Bouman, A., Yamada, A., Levy, M., Dingemans, A.J., de Vries, B.B.,... Kleefstra, T. (2024). Comprehensive EHMT1 variants analysis broadens genotype-phenotype associations and molecular mechanisms in Kleefstra syndrome. American Journal of Human Genetics, 111(8), 1605-1625. https://doi.org/10.1016/j.ajhg.2024.06.008

MLA:

Rots, Dmitrijs, et al. "Comprehensive EHMT1 variants analysis broadens genotype-phenotype associations and molecular mechanisms in Kleefstra syndrome." American Journal of Human Genetics 111.8 (2024): 1605-1625.

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