- Browse by Author
Browsing by Author "Douglas, Ganka"
Now showing 1 - 2 of 2
Results Per Page
Sort Options
Item Missense variants in TAF1 and developmental phenotypes: Challenges of determining pathogenicity(Wiley, 2019-10-23) Cheng, Hanyin; Capponi, Simona; Wakeling, Emma; Marchi, Elaine; Li, Quan; Zhao, Mengge; Weng, Chunhua; Piatek, Stefan G.; Ahlfors, Helena; Kleyner, Robert; Rope, Alan; Lumaka, Aimé; Lukusa, Prosper; Devriendt, Koenraad; Vermeesch, Joris; Posey, Jennifer E.; Palmer, Elizabeth E.; Murray, Lucinda; Leon, Eyby; Diaz, Jullianne; Worgan, Lisa; Mallawaarachchi, Amali; Vogt, Julie; de Munnik, Sonja A.; Dreyer, Lauren; Baynam, Gareth; Ewans, Lisa; Stark, Zornitza; Lunke, Sebastian; Gonçalves, Ana R.; Soares, Gabriela; Oliveira, Jorge; Fassi, Emily; Willing, Marcia; Waugh, Jeff L.; Faivre, Laurence; Riviere, Jean-Baptiste; Moutton, Sebastien; Mohammed, Shehla; Payne, Katelyn; Walsh, Laurence; Begtrup, Amber; Guillen Sacoto, Maria J.; Douglas, Ganka; Alexander, Nora; Buckley, Michael F.; Mark, Paul R.; Adès, Lesley C.; Sandaradura, Sarah A.; Lupski, James R.; Roscioli, Tony; Agrawal, Pankaj B.; Kline, Antonie D.; Wang, Kai; Timmers, T. Marc; Lyon, Gholson J.; Neurology, School of MedicineWe recently described a new neurodevelopmental syndrome (TAF1/MRXS33 intellectual disability syndrome) (MIM# 300966) caused by pathogenic variants involving the X-linked gene TAF1, which participates in RNA polymerase II transcription. The initial study reported eleven families, and the syndrome was defined as presenting early in life with hypotonia, facial dysmorphia, and developmental delay that evolved into intellectual disability (ID) and/or autism spectrum disorder (ASD). We have now identified an additional 27 families through a genotype-first approach. Familial segregation analysis, clinical phenotyping, and bioinformatics were capitalized on to assess potential variant pathogenicity, and molecular modelling was performed for those variants falling within structurally characterized domains of TAF1. A novel phenotypic clustering approach was also applied, in which the phenotypes of affected individuals were classified using 51 standardized Human Phenotype Ontology (HPO) terms. Phenotypes associated with TAF1 variants show considerable pleiotropy and clinical variability, but prominent among previously unreported effects were brain morphological abnormalities, seizures, hearing loss, and heart malformations. Our allelic series broadens the phenotypic spectrum of TAF1/MRXS33 intellectual disability syndrome and the range of TAF1 molecular defects in humans. It also illustrates the challenges for determining the pathogenicity of inherited missense variants, particularly for genes mapping to chromosome X.Item 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 MedicineWe 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.