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

TitleDelineating the molecular and phenotypic spectrum of the SETD1B-related syndrome.
Publication TypeJournal Article
Year of Publication2021
AuthorsWeerts, MJA, Lanko, K, Guzmán-Vega, FJ, Jackson, A, Ramakrishnan, R, Cardona-Londoño, KJ, Peña-Guerra, KA, van Bever, Y, van Paassen, BW, Kievit, A, van Slegtenhorst, M, Allen, NM, Kehoe, CM, Robinson, HK, Pang, L, Banu, SH, Zaman, M, Efthymiou, S, Houlden, H, Järvelä, I, Lauronen, L, Määttä, T, Schrauwen, I, Leal, SM, Ruivenkamp, CAL, Barge-Schaapveld, DQCM, Peeters-Scholte, CMPCD, Galehdari, H, Mazaheri, N, Sisodiya, SM, Harrison, V, Sun, A, Thies, J, Pedroza, LAlberto, Lara-Taranchenko, Y, Chinn, IK, Lupski, JR, Garza-Flores, A, McGlothlin, J, Yang, L, Huang, S, Wang, X, Jewett, T, Rosso, G, Lin, X, Mohammed, S, J Merritt, L, Mirzaa, GM, Timms, AE, Scheck, J, Elting, MW, Polstra, AM, Schenck, L, Ruzhnikov, MRZ, Vetro, A, Montomoli, M, Guerrini, R, Koboldt, DC, Mosher, TMihalic, Pastore, MT, McBride, KL, Peng, J, Pan, Z, Willemsen, M, Koning, S, Turnpenny, PD, de Vries, BBA, Gilissen, C, Pfundt, R, Lees, M, Braddock, SR, Klemp, KC, Vansenne, F, van Gijn, ME, Quindipan, C, Deardorff, MA, J Hamm, A, Putnam, AM, Baud, R, Walsh, L, Lynch, SA, Baptista, J, Person, RE, Monaghan, KG, Crunk, A, Keller-Ramey, J, Reich, A, Elloumi, HZghal, Alders, M, Kerkhof, J, McConkey, H, Haghshenas, S, Maroofian, R, Sadikovic, B, Banka, S, Arold, ST, Barakat, TStefan
Corporate AuthorsGenomics England Research Consortium
JournalGenet Med
Volume23
Issue11
Pagination2122-2137
Date Published2021 11
ISSN1530-0366
KeywordsEpilepsy, Histone-Lysine N-Methyltransferase, Humans, Intellectual Disability, Male, Neurodevelopmental Disorders, Phenotype, Seizures
Abstract

PURPOSE: 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.

METHODS: We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum.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.

RESULTS: 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.

CONCLUSION: Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.

DOI10.1038/s41436-021-01246-2
Alternate JournalGenet Med
PubMed ID34345025
PubMed Central IDPMC8553606
Grant ListVeni 91617021 / ZONMW_ / ZonMw / Netherlands
P50 HD103524 / HD / NICHD NIH HHS / United States
MR/S005021/1 / MRC_ / Medical Research Council / United Kingdom
UM1 HG006542 / HG / NHGRI NIH HHS / United States
MR/S01165X/1 / MRC_ / Medical Research Council / United Kingdom
ZONMW_91617021 / ZONMW_ / ZonMw / Netherlands
/ WT_ / Wellcome Trust / United Kingdom
G0601943 / MRC_ / Medical Research Council / United Kingdom