|Title||Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome.|
|Publication Type||Journal Article|
|Year of Publication||2021|
|Authors||Weerts, 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 Authors||Genomics England Research Consortium|
|Date Published||2021 11|
|Keywords||Epilepsy, Histone-Lysine N-Methyltransferase, Humans, Intellectual Disability, Male, Neurodevelopmental Disorders, Phenotype, Seizures|
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METHODS: We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum.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.
|Alternate Journal||Genet Med|
|PubMed Central ID||PMC8553606|
|Grant List||Veni 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