Delineating the clinical and molecular spectrum of the neurodevelopmental disorder associated with SET.

Authors

Yuwei Shi, Ananilia Silva, Christophe Debuy, Sourav Ghosh, Haley McConkey, Rachel Schot, Ruizhi Deng, Anita Nikoncuk, Marjon van Slegtenhorst, Lies H Hoefsloot, Tjakko J van Ham, Brittany N Simpson, Dana Miller, Nishitha R Pillai, Muriel Holder-Espinasse, Berta Almoguera, Fiona Blanco-Kelly, Virginia Clowes, Grace Yoon, Berrin Monteleone, Jaime Vasquez, Rubén Pérez de la Fuente, Sara Bellido-Cuéllar, Ursino Barrios-Machain, Yolanda Moreno-Sáez, Katharina Steindl, Anais Begemann, Anita Rauch, Tiffany Busa, Svetlana Gorokhova, Shenela Lakhani, Zachary Grinspan, Aurore Garde, Frederic Tran Mau Them, Ange-Line Bruel, Julian Delanne, Hana Safraou, Estelle Colin, Aditi Shah Parikh, Anne Slavotinek, Patrick Devine, Amelle Shillington, Arthur Sorlin, Didier Menzies, Lakshmi Mehta, Charlotte Close, Caleb Heid, Syed Ajaz Ahmed, Adriana Gomes, Lynne M Bird, Erfan Aref-Eshghi, Kelly J Cardona-Londoño, Stefan T Arold, Jing-Mei Li, Tzung-Chien Hsieh, Tjitske Kleefstra, Kristina Lanko, Bekim Sadikovic, Tahsin Stefan Barakat

Published in

Genetics in medicine : official journal of the American College of Medical Genetics. Pages 102637. Jun 19, 2026. Epub Jun 19, 2026.

Abstract

SET is a member of the inhibitor of histone acetyltransferases (INHAT) complex, involved in transcriptional silencing and gene regulation. Pathogenic variants in SET are postulated to cause neurodevelopmental disorder (NDD) phenotypes, but as only few individuals are described, detailed clinical information is scarce. Hence, currently counseling on phenotype and prognosis of this condition remains challenging.
Here we describe the clinical phenotype and mutational spectrum of 23 unreported individuals harboring (likely) pathogenic variants in SET.
Phenotypes include global developmental delay with often pronounced hypotonia, delayed motor development and speech and language delay, ultimately evolving into (mild) intellectual disability. Comorbidities include behavioral concerns, sleeping disturbance and variable unspecific ocular problems. Next generation computer-assisted phenotyping using GestaltMatcher showed limited overlapping facial features between affected individuals and differences compared to disorders caused by related chromatin modifying genes. In addition, we generated a DNA methylation signature, able to distinguish individuals carrying pathogenic variants in SET from individuals with other NDDs and healthy controls. We used this DNA methylation signature to assess pathogenicity of two variants of uncertain significance in SET found in two additional individuals.
Together, this expands the knowledge on the SET-related disorder and provides novel approaches for its diagnosis.

PMID:
42322191
Bibliographic data and abstract were imported from PubMed on 20 Jun 2026.

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