Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

Marjolein J A Weerts; Kristina Lanko; Francisco J Guzmán-Vega; Adam Jackson; Reshmi Ramakrishnan; Kelly J Cardona-Londoño; Karla A Peña-Guerra; Yolande van Bever; Barbara W van Paassen; Anneke Kievit; Marjon van Slegtenhorst; Nicholas M Allen; Caroline M Kehoe; Hannah K Robinson; Lewis Pang; Selina H Banu; Mashaya Zaman; Stephanie Efthymiou; Henry Houlden; Irma Järvelä; Leena Lauronen; Tuomo Määttä; Isabelle Schrauwen; Suzanne M Leal; Claudia A L Ruivenkamp; Daniela Q C M Barge-Schaapveld; Cacha M P C D Peeters-Scholte; Hamid Galehdari; Neda Mazaheri; Sanjay M Sisodiya; Victoria Harrison; Angela Sun; Jenny Thies; Luis Alberto Pedroza; Yana Lara-Taranchenko; Ivan K Chinn; James R Lupski; Alexandra Garza-Flores; Jeffery McGlothlin; Lin Yang; Shaoping Huang; Xiaodong Wang; Tamison Jewett; Gretchen Rosso; Xi Lin; Shehla Mohammed; J Lawrence Merritt, 2nd; Ghayda M Mirzaa; Andrew E Timms; Joshua Scheck; Mariet W Elting; Abeltje M Polstra; Lauren Schenck; Maura R Z Ruzhnikov; Annalisa Vetro; Martino Montomoli; Renzo Guerrini; Daniel C Koboldt; Theresa Mihalic Mosher; Matthew T Pastore; Kim L McBride; Jing Peng; Zou Pan; Marjolein Willemsen; Susanne Koning; Peter D Turnpenny; Bert B A de Vries; Christian Gilissen; Rolph Pfundt; Melissa Lees; Stephen R Braddock; Kara C Klemp; Fleur Vansenne; Marielle E van Gijn; Catherine Quindipan; Matthew A Deardorff; J Austin Hamm; Abbey M Putnam; Rebecca Baud; Laurence Walsh; Sally A Lynch; Julia Baptista; Richard E Person; Kristin G Monaghan; Amy Crunk; Jennifer Keller-Ramey; Adi Reich; Houda Zghal Elloumi; Marielle Alders; Jennifer Kerkhof; Haley McConkey; Sadegheh Haghshenas; Reza Maroofian; Bekim Sadikovic; Siddharth Banka; Stefan T Arold; Tahsin Stefan Barakat; Genomics England Research Consortium

doi:10.1038/s41436-021-01246-2

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Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

Journal article

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Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

Marjolein J A Weerts, Kristina Lanko, Francisco J Guzmán-Vega, Adam Jackson, Reshmi Ramakrishnan, Kelly J Cardona-Londoño, Karla A Peña-Guerra, Yolande van Bever, Barbara W van Paassen, Anneke Kievit, …

Genetics in medicine, Vol.23(11), pp.2122-2137

01/11/2021

DOI: https://doi.org/10.1038/s41436-021-01246-2

PMCID: 8553606

PMID: 34345025

Abstract

Epilepsy - diagnosis

Epilepsy - genetics

Histone-Lysine N-Methyltransferase - genetics

Humans

Intellectual Disability - diagnosis

Intellectual Disability - genetics

Male

Neurodevelopmental Disorders - diagnosis

Neurodevelopmental Disorders - genetics

Phenotype

Seizures - diagnosis

Seizures - genetics

Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort. We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.

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Title: Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome
Creators - without role: Marjolein J A Weerts - Erasmus MC
Kristina Lanko - Erasmus MC
Francisco J Guzmán-Vega - King Abdullah University of Science and Technology
Adam Jackson - St Mary's Hospital
Reshmi Ramakrishnan - King Abdullah University of Science and Technology
Kelly J Cardona-Londoño - King Abdullah University of Science and Technology
Karla A Peña-Guerra - King Abdullah University of Science and Technology
Yolande van Bever - Erasmus MC
Barbara W van Paassen - Erasmus MC
Anneke Kievit - Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands
Marjon van Slegtenhorst - Erasmus MC
Nicholas M Allen - Ollscoil na Gaillimhe – University of Galway
Caroline M Kehoe - Ollscoil na Gaillimhe – University of Galway
Hannah K Robinson - Royal Devon & Exeter NHS Foundation Trust
Lewis Pang - Royal Devon & Exeter NHS Foundation Trust
Selina H Banu - Dhaka Shishu Hospital
Mashaya Zaman - Dhaka Shishu Hospital
Stephanie Efthymiou - National Hospital for Neurology and Neurosurgery
Henry Houlden - National Hospital for Neurology and Neurosurgery
Irma Järvelä - University of Helsinki
Leena Lauronen - University of Helsinki
Tuomo Määttä - Kajaani University of Applied Sciences
Isabelle Schrauwen - Columbia University Irving Medical Center
Suzanne M Leal - Columbia University Irving Medical Center
Claudia A L Ruivenkamp - Leiden University Medical Center
Daniela Q C M Barge-Schaapveld - Leiden University Medical Center
Cacha M P C D Peeters-Scholte - Leiden University Medical Center
Hamid Galehdari - Shahid Chamran University of Ahvaz
Neda Mazaheri - Shahid Chamran University of Ahvaz
Sanjay M Sisodiya - National Hospital for Neurology and Neurosurgery
Victoria Harrison - Princess Anne Hospital
Angela Sun - University of Washington
Jenny Thies - Seattle Children's Hospital
Luis Alberto Pedroza - Columbia University
Yana Lara-Taranchenko - Universidad San Francisco de Quito
Ivan K Chinn - Baylor College of Medicine
James R Lupski - Baylor College of Medicine
Alexandra Garza-Flores - Cook Children's Medical Center
Jeffery McGlothlin - Cook Children's Medical Center
Lin Yang - Second Affiliated Hospital of Xi'an Jiaotong University
Shaoping Huang - Second Affiliated Hospital of Xi'an Jiaotong University
Xiaodong Wang - Cipher Gene
Tamison Jewett - Wake Forest University
Gretchen Rosso - Wake Forest University
Xi Lin - First Affiliated Hospital of Fujian Medical University
Shehla Mohammed - Guy's and St Thomas' NHS Foundation Trust
J Lawrence Merritt, 2nd - University of Washington School of Medicine
Ghayda M Mirzaa - University of Washington
Andrew E Timms - Seattle Children's Hospital
Joshua Scheck - Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA
Mariet W Elting - Amsterdam UMC Location VUmc
Abeltje M Polstra - Amsterdam UMC Location VUmc
Lauren Schenck - Stanford Medicine
Maura R Z Ruzhnikov - Stanford Medicine
Annalisa Vetro - Meyer Children's Hospital
Martino Montomoli - Meyer Children's Hospital
Renzo Guerrini - Meyer Children's Hospital
Daniel C Koboldt - Nationwide Children's Hospital
Theresa Mihalic Mosher - Nationwide Children's Hospital
Matthew T Pastore - Nationwide Children's Hospital
Kim L McBride - Nationwide Children's Hospital
Jing Peng - Xiangya Hospital Central South University
Zou Pan - Xiangya Hospital Central South University
Marjolein Willemsen - Radboud University Nijmegen
Susanne Koning - Maastricht University
Peter D Turnpenny - Royal Devon & Exeter NHS Foundation Trust
Bert B A de Vries - Radboud University Nijmegen
Christian Gilissen - Radboud University Nijmegen
Rolph Pfundt - Radboud University Nijmegen
Melissa Lees - Great Ormond Street Hospital for Children NHS Foundation Trust
Stephen R Braddock - Cardinal Glennon Children’s Medical Center
Kara C Klemp - Cardinal Glennon Children’s Medical Center
Fleur Vansenne - University Medical Center Groningen
Marielle E van Gijn - University Medical Center Groningen
Catherine Quindipan - Children's Hospital of Los Angeles
Matthew A Deardorff - Children's Hospital of Los Angeles
J Austin Hamm - East Tennessee Children's Hospital
Abbey M Putnam - East Tennessee Children's Hospital
Rebecca Baud - Indiana University
Laurence Walsh - Indiana University
Sally A Lynch - Children's Health Ireland at Crumlin
Julia Baptista - Royal Devon & Exeter NHS Foundation Trust
Richard E Person - GeneDx, Gaithersburg, MD, USA
Kristin G Monaghan - GeneDx, Gaithersburg, MD, USA
Amy Crunk - GeneDx, Gaithersburg, MD, USA
Jennifer Keller-Ramey - GeneDx, Gaithersburg, MD, USA
Adi Reich - GeneDx, Gaithersburg, MD, USA
Houda Zghal Elloumi - GeneDx, Gaithersburg, MD, USA
Marielle Alders - University of Amsterdam
Jennifer Kerkhof - London Health Sciences Centre
Haley McConkey - London Health Sciences Centre
Sadegheh Haghshenas - Western University
Reza Maroofian - University College London
Bekim Sadikovic - London Health Sciences Centre
Siddharth Banka - Manchester University NHS Foundation Trust
Stefan T Arold - King Abdullah University of Science and Technology
Tahsin Stefan Barakat - Erasmus MC
Genomics England Research Consortium
Publication Details: Genetics in medicine, Vol.23(11), pp.2122-2137
Grant note: P50 HD103524 / NICHD NIH HHS G0601943 / Medical Research Council Veni 91617021 / ZonMw MR/S005021/1 / Medical Research Council Wellcome Trust 91617021 / ZonMw UM1 HG006542 / NHGRI NIH HHS MR/S01165X/1 / Medical Research Council
Identifiers: 9941308008331
Academic Unit: King Abdullah University of Science & Technology
Language: English
Resource Type: Journal article