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DOI 10.1038/s41436-021-01246-2

Медицинская библиотека · Genetics in medicine : official journal of the American College of Medical Genetics · 2021

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

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

СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАПеревод в очереди

Аннотация

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.

Для цитирования: Weerts Marjolein J A, Lanko Kristina, Guzmán-Vega Francisco J, Jackson Adam, Ramakrishnan Reshmi, Cardona-Londoño Kelly J, Peña-Guerra Karla A, van Bever Yolande, van Paassen Barbara W, Kievit Anneke, van Slegtenhorst Marjon, Allen Nicholas M, Kehoe Caroline M, Robinson Hannah K, Pang Lewis, Banu Selina H, Zaman Mashaya, Efthymiou Stephanie, Houlden Henry, Järvelä Irma, Lauronen Leena, Määttä Tuomo, Schrauwen Isabelle, Leal Suzanne M, Ruivenkamp Claudia A L, Barge-Schaapveld Daniela Q C M, Peeters-Scholte Cacha M P C D, Galehdari Hamid, Mazaheri Neda, Sisodiya Sanjay M, Harrison Victoria, Sun Angela, Thies Jenny, Pedroza Luis Alberto, Lara-Taranchenko Yana, Chinn Ivan K, Lupski James R, Garza-Flores Alexandra, McGlothlin Jeffery, Yang Lin, Huang Shaoping, Wang Xiaodong, Jewett Tamison, Rosso Gretchen, Lin Xi, Mohammed Shehla, Merritt J Lawrence, Mirzaa Ghayda M, Timms Andrew E, Scheck Joshua, Elting Mariet W, Polstra Abeltje M, Schenck Lauren, Ruzhnikov Maura R Z, Vetro Annalisa, Montomoli Martino, Guerrini Renzo, Koboldt Daniel C, Mosher Theresa Mihalic, Pastore Matthew T, McBride Kim L, Peng Jing, Pan Zou, Willemsen Marjolein, Koning Susanne, Turnpenny Peter D, de Vries Bert B A, Gilissen Christian, Pfundt Rolph, Lees Melissa, Braddock Stephen R, Klemp Kara C, Vansenne Fleur, van Gijn Marielle E, Quindipan Catherine, Deardorff Matthew A, Hamm J Austin, Putnam Abbey M, Baud Rebecca, Walsh Laurence, Lynch Sally A, Baptista Julia, Person Richard E, Monaghan Kristin G, Crunk Amy, Keller-Ramey Jennifer, Reich Adi, Elloumi Houda Zghal, Alders Marielle, Kerkhof Jennifer, McConkey Haley, Haghshenas Sadegheh, Genomics England Research Consortium, Maroofian Reza, Sadikovic Bekim, Banka Siddharth, Arold Stefan T, Barakat Tahsin Stefan. Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome.. Genetics in medicine : official journal of the American College of Medical Genetics. 2021. DOI: 10.1038/s41436-021-01246-2.

Предметные рубрики MeSH

EpilepsyHistone-Lysine N-MethyltransferaseHumansIntellectual DisabilityMaleNeurodevelopmental DisordersPhenotypeSeizures
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