Browsing by Author "van Gassen, Koen L.I."

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    Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior
    (Elsevier, 2021) Harris, Holly K.; Nakayama, Tojo; Lai, Jenny; Zhao, Boxun; Argyrou, Nikoleta; Gubbels, Cynthia S.; Soucy, Aubrie; Genetti, Casie A.; Suslovitch, Victoria; Rodan, Lance H.; Tiller, George E.; Lesca, Gaetan; Gripp, Karen W.; Asadollahi, Reza; Hamosh, Ada; Applegate, Carolyn D.; Turnpenny, Peter D.; Simon, Marleen E.H.; Volker-Touw, Catharina M.L.; van Gassen, Koen L.I.; van Binsbergen, Ellen; Pfundt, Rolph; Gardeitchik, Thatjana; de Vries, Bert B.A.; Immken, LaDonna L.; Buchanan, Catherine; Willing, Marcia; Toler, Tomi L.; Fassi, Emily; Baker, Laura; Vansenne, Fleur; Wang, Xiadong; Ambrus, Julian L., Jr.; Fannemel, Madeleine; Posey, Jennifer E.; Agolini, Emanuele; Novelli, Antonio; Rauch, Anita; Boonsawat, Paranchai; Fagerberg, Christina R.; Larsen, Martin J.; Kibaek, Maria; Labalme, Audrey; Poisson, Alice; Payne, Katelyn K.; Walsh, Laurence E.; Aldinger, Kimberly A.; Balciuniene, Jorune; Skraban, Cara; Gray, Christopher; Murrell, Jill; Bupp, Caleb P.; Pascolini, Giulia; Grammatico, Paola; Broly, Martin; Küry, Sébastien; Nizon, Mathilde; Rasool, Iqra Ghulam; Zahoor, Muhammad Yasir; Kraus, Cornelia; Reis, André; Iqbal, Muhammad; Uguen, Kevin; Audebert-Bellanger, Severine; Ferec, Claude; Redon, Sylvia; Baker, Janice; Wu, Yunhong; Zampino, Guiseppe; Syrbe, Steffan; Brosse, Ines; Jamra, Rami Abou; Dobyns, William B.; Cohen, Lilian L.; Blomhoff, Anne; Mignot, Cyril; Keren, Boris; Courtin, Thomas; Agrawal, Pankaj B.; Beggs, Alan H.; Yu, Timothy W.; Neurology, School of Medicine
    Purpose: We describe a novel neurobehavioral phenotype of autism spectrum disorder (ASD), intellectual disability, and/or attention-deficit/hyperactivity disorder (ADHD) associated with de novo or inherited deleterious variants in members of the RFX family of genes. RFX genes are evolutionarily conserved transcription factors that act as master regulators of central nervous system development and ciliogenesis. Methods: We assembled a cohort of 38 individuals (from 33 unrelated families) with de novo variants in RFX3, RFX4, and RFX7. We describe their common clinical phenotypes and present bioinformatic analyses of expression patterns and downstream targets of these genes as they relate to other neurodevelopmental risk genes. Results: These individuals share neurobehavioral features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. Conclusion: These results establish a likely role of deleterious variation in RFX3, RFX4, and RFX7 in cases of monogenic intellectual disability, ADHD and ASD, and position these genes as potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.
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    WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features
    (Elsevier, 2017-07-06) Skraban, Cara M.; Wells, Constance F.; Markose, Preetha; Cho, Megan T.; Nesbitt, Addie I.; Au, P.Y. Billie; Begtrup, Amber; Bernat, John A.; Bird, Lynne M.; Cao, Kajia; de Brouwer, Arjan P.M.; Denenberg, Elizabeth H.; Douglas, Ganka; Gibson, Kristin M.; Grand, Katheryn; Goldenberg, Alice; Innes, A. Micheil; Juusola, Jane; Kempers, Marlies; Kinning, Esther; Markie, David M.; Owens, Martina M.; Payne, Katelyn; Person, Richard; Pfundt, Rolph; Stocco, Amber; Turner, Claire L.S.; Verbeek, Nienke E.; Walsh, Laurence E.; Warner, Taylor C.; Wheeler, Patricia G.; Wieczorek, Dagmar; Wilkens, Alisha B.; Zonneveld-Huijssoon, Evelien; Deciphering Developmental Disorders Study; Kleefstra, Tjitske; Robertson, Stephen P.; Santani, Avni; van Gassen, Koen L.I.; Deardorf, Matthew A.; Pediatrics, School of Medicine
    We report 15 individuals with de novo pathogenic variants in WDR26. Eleven of the individuals carry loss-of-function mutations, and four harbor missense substitutions. These 15 individuals comprise ten females and five males, and all have intellectual disability with delayed speech, a history of febrile and/or non-febrile seizures, and a wide-based, spastic, and/or stiff-legged gait. These subjects share a set of common facial features that include a prominent maxilla and upper lip that readily reveal the upper gingiva, widely spaced teeth, and a broad nasal tip. Together, these features comprise a recognizable facial phenotype. We compared these features with those of chromosome 1q41q42 microdeletion syndrome, which typically contains WDR26, and noted that clinical features are consistent between the two subsets, suggesting that haploinsufficiency of WDR26 contributes to the pathology of 1q41q42 microdeletion syndrome. Consistent with this, WDR26 loss-of-function single-nucleotide mutations identified in these subjects lead to nonsense-mediated decay with subsequent reduction of RNA expression and protein levels. We derived a structural model of WDR26 and note that missense variants identified in these individuals localize to highly conserved residues of this WD-40-repeat-containing protein. Given that WDR26 mutations have been identified in ∼1 in 2,000 of subjects in our clinical cohorts and that WDR26 might be poorly annotated in exome variant-interpretation pipelines, we would anticipate that this disorder could be more common than currently appreciated.