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

Dmitrijs Rots, Arianne Bouman, Ayumi Yamada, Michael Levy, Alexander J.M. Dingemans, Bert B.A. de Vries, Martina Ruiterkamp-Versteeg, Nicole de Leeuw, Charlotte W. Ockeloen, Rolph Pfundt, Elke de Boer, Joost Kummeling, Bregje van Bon, Hans van Bokhoven, Nael Nadif Kasri, Hanka Venselaar, Marielle Alders, Jennifer Kerkhof, Haley McConkey, Alma KuechlerBart Elffers, Rixje van Beeck Calkoen, Susanna Hofman, Audrey Smith, Maria Irene Valenzuela, Siddharth Srivastava, Zoe Frazier, Isabelle Maystadt, Carmelo Piscopo, Giuseppe Merla, Meena Balasubramanian, Gijs W.E. Santen, Kay Metcalfe, Soo Mi Park, Laurent Pasquier, Siddharth Banka, Dian Donnai, Daniel Weisberg, Gertrud Strobl-Wildemann, Annemieke Wagemans, Maaike Vreeburg, Diana Baralle, Nicola Foulds, Ingrid Scurr, Nicola Brunetti-Pierri, Johanna M. van Hagen, Emilia K. Bijlsma, Anna H. Hakonen, Carolina Courage, David Genevieve, Lucile Pinson, Francesca Forzano, Charu Deshpande, Maria L. Kluskens, Lindsey Welling, Astrid S. Plomp, Els K. Vanhoutte, Louisa Kalsner, Janna A. Hol, Audrey Putoux, Johanna Lazier, Pradeep Vasudevan, Elizabeth Ames, Jessica O'Shea, Damien Lederer, Julie Fleischer, Mary O'Connor, Melissa Pauly, Georgia Vasileiou, André Reis, Catherine Kiraly-Borri, Arjan Bouman, Chris Barnett, Marjan Nezarati, Lauren Borch, Gea Beunders, Kübra Özcan, Stéphanie Miot, Catharina M.L. Volker-Touw, Koen L.I. van Gassen, Gerarda Cappuccio, Katrien Janssens, Nofar Mor, Inna Shomer, Dan Dominissini, Matthew L. Tedder, Alison M. Muir, Bekim Sadikovic, Han G. Brunner, Lisenka E.L.M. Vissers, Yoichi Shinkai, Tjitske Kleefstra

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

Abstrakti

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.

Alkuperäiskielienglanti
LehtiAmerican Journal of Human Genetics
Vuosikerta111
Numero8
Sivut1605-1625
Sivumäärä21
ISSN0002-9297
DOI - pysyväislinkit
TilaJulkaistu - 8 elok. 2024
OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu

Lisätietoja

Publisher Copyright:
© 2024 American Society of Human Genetics

Tieteenalat

  • 1184 Genetiikka, kehitysbiologia, fysiologia

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