WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features

• Published in: American journal of human genetics Vol. 101; no. 1; pp. 139 - 148
• Main Authors: 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, Kleefstra, Tjitske, Robertson, Stephen P., Santani, Avni, van Gassen, Koen L.I., Deardorff, Matthew A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06-07-2017; Elsevier
• Subjects: Amino Acid Sequence; Base Sequence; Child, Preschool; Chromosome Deletion; Facies; Female; Gait - genetics; Growth and Development - genetics; Haploinsufficiency - genetics; Humans; intellectual disability; Intellectual Disability - complications; Intellectual Disability - genetics; Male; Mutation - genetics; Proteins - chemistry; Proteins - genetics; RNA Stability - genetics; seizure; Seizures - complications; Seizures - genetics; Syndrome; WD-40; WDR protein; WDR26; WDR protein; WDR26; seizure; WD-40; intellectual disability
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2017.06.002

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.