作者
Dmitrijs Rots,Arianne Bouman,Ayumi Yamada,Michael A. 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 W.M. van Bon,Hans van Bokhoven,Nael Nadif Kasri,Hanka Venselaar,Mariëlle Alders,Jennifer Kerkhof,Haley McConkey,Alma Kuechler,Bart Elffers,Rixje van Beeck Calkoen,Susanna Hofman,Audrey Smith,Irene Valenzuela,Siddharth Srivastava,Zoë 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 Geneviève,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 Omark O’Shea,Damien Lederer,Julie Fleischer,Mary O’Connor,M. Pauly,Georgia Vasileiou,André Reis,Cathy Kiraly‐Borri,Arjan Bouman,Chris Barnett,Marjan M. 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 Sadiković,Han G. Brunner,Lisenka E.L.M. Vissers,Yoichi Shinkai,Tjitske Kleefstra
摘要
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.