Delineating the clinical and molecular spectrum of the neurodevelopmental disorder associated with SET.
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Shi Yuwei, Silva Ananilia, Debuy Christophe, Ghosh Sourav, McConkey Haley, Schot Rachel, Deng Ruizhi, Nikoncuk Anita, van Slegtenhorst Marjon, Hoefsloot Lies H, van Ham Tjakko J, Simpson Brittany N, Miller Dana, Pillai Nishitha R, Holder-Espinasse Muriel, Almoguera Berta, Blanco-Kelly Fiona, Clowes Virginia, Yoon Grace, Monteleone Berrin, Vasquez Jaime, Pérez de la Fuente Rubén, Bellido-Cuéllar Sara, Barrios-Machain Ursino, Moreno-Sáez Yolanda, Steindl Katharina, Begemann Anais, Rauch Anita, Busa Tiffany, Gorokhova Svetlana, Lakhani Shenela, Grinspan Zachary, Garde Aurore, Mau Them Frederic Tran, Bruel Ange-Line, Delanne Julian, Safraou Hana, Colin Estelle, Parikh Aditi Shah, Slavotinek Anne, Devine Patrick, Shillington Amelle, Sorlin Arthur, Menzies Didier, Mehta Lakshmi, Close Charlotte, Heid Caleb, Ahmed Syed Ajaz, Gomes Adriana, Bird Lynne M, Aref-Eshghi Erfan, Cardona-Londoño Kelly J, Arold Stefan T, Li Jing-Mei, Hsieh Tzung-Chien, Kleefstra Tjitske, Lanko Kristina, Sadikovic Bekim, Barakat Tahsin Stefan
Аннотация
METHODS: Here, we describe the clinical phenotype and mutational spectrum of 23 unreported individuals harboring (likely) pathogenic variants in SET.
RESULTS: Phenotypes include global developmental delay, often with pronounced hypotonia, delayed motor development, and speech and language delay, ultimately evolving into (mild) intellectual disability. Comorbidities include behavioral concerns, sleep disturbances, and variable nonspecific ocular problems. Next-generation computer-assisted phenotyping using GestaltMatcher showed limited overlapping facial features between affected individuals and differences compared with disorders caused by related chromatin-modifying genes in individuals. In addition, we generated a DNA methylation signature able to distinguish individuals carrying pathogenic variants in SET from individuals with other neurodevelopmental disorders and healthy controls. We used this DNA methylation signature to assess the pathogenicity of 2 variants of uncertain clinical significance in SET found in 2 additional individuals.
CONCLUSION: Together, this expands the knowledge on SET-related disorders and provides novel approaches for their diagnosis.