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

表型 基因型 遗传学 生物 基因型-表型区分 基因
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
出处
期刊:American Journal of Human Genetics [Elsevier]
被引量:1
标识
DOI:10.1016/j.ajhg.2024.06.008
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.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
曾经电源完成签到,获得积分20
1秒前
BOLIN完成签到,获得积分10
2秒前
2秒前
ding应助等待思远采纳,获得10
3秒前
方方完成签到 ,获得积分10
3秒前
zzuwxj完成签到,获得积分10
3秒前
旁白完成签到,获得积分10
3秒前
橙橙橙完成签到,获得积分10
5秒前
vickeylea完成签到,获得积分10
6秒前
6秒前
77完成签到 ,获得积分10
9秒前
旁白发布了新的文献求助10
10秒前
11秒前
@你。完成签到 ,获得积分10
11秒前
Ava应助井莹采纳,获得10
13秒前
直率书芹完成签到,获得积分10
13秒前
perfect完成签到 ,获得积分10
16秒前
17秒前
小芳芳完成签到 ,获得积分10
18秒前
柒月发布了新的文献求助10
21秒前
萝卜猪完成签到,获得积分10
22秒前
123应助寒冷的断秋采纳,获得10
22秒前
23秒前
南宫清涟完成签到 ,获得积分10
25秒前
YOMU完成签到,获得积分10
25秒前
炙热的萤完成签到,获得积分20
25秒前
26秒前
Dream完成签到,获得积分0
28秒前
张颖完成签到 ,获得积分10
28秒前
28秒前
炙热的萤发布了新的文献求助10
29秒前
加减乘除发布了新的文献求助10
29秒前
深情口红完成签到,获得积分10
29秒前
企鹅公路关注了科研通微信公众号
29秒前
fzm完成签到,获得积分10
30秒前
英俊枫完成签到,获得积分10
31秒前
couletian完成签到 ,获得积分10
31秒前
暴富完成签到,获得积分10
31秒前
坚定龙猫完成签到,获得积分10
33秒前
沙与沫完成签到 ,获得积分10
33秒前
高分求助中
Evolution 10000
ISSN 2159-8274 EISSN 2159-8290 1000
Becoming: An Introduction to Jung's Concept of Individuation 600
Ore genesis in the Zambian Copperbelt with particular reference to the northern sector of the Chambishi basin 500
A new species of Coccus (Homoptera: Coccoidea) from Malawi 500
A new species of Velataspis (Hemiptera Coccoidea Diaspididae) from tea in Assam 500
PraxisRatgeber: Mantiden: Faszinierende Lauerjäger 500
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3162539
求助须知:如何正确求助?哪些是违规求助? 2813402
关于积分的说明 7900247
捐赠科研通 2472973
什么是DOI,文献DOI怎么找? 1316615
科研通“疑难数据库(出版商)”最低求助积分说明 631375
版权声明 602175