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PgmNr 73: De novo variants in WDR37 are associated with epilepsy, colobomas, dysmorphism, developmental delay, intellectual disability, and cerebellar hypoplasia.

O. Kanca 1; J.C. Andrews 1; P.T. Lee 1; C. Patel 2; S. Braddock 3,4; A.M. Slavotinek 5; J.S. Cohen 6; C.S. Gubbels 7; K.A. Aldinger 8; J. Williams 9; M. Indaram 10; A. Fatemi 6; T.W. Yu 7; P.B. Agrawal 11; G. Vezina 12; B. Gangaram 5; J. Wynn 13; R. Hernan 13; G. Mychaliska 22; W.K. Chung 13; T.C. Markello 14,15; W.B. Dobyns 8,16,17; D.R. Adams 14,15; W.A. Gahl 14,15; M.F. Wangler 1,18,19; S. Yamamoto 1,18,19,20; H.J. Bellen 1,18,19,20,21; M.C.V. Malicdan 14,15; Undiagnosed Disease Network

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1) Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.; 2) Genetic Health Queensland, Royal Brisbane and Women’s Hospital, Brisbane, QLD 4029, Australia; 3) Department of Pediatrics, Cardinal Glennon Children's Medical Center, St. Louis, MO, 63104, USA; 4) Division of Pediatric Medical Genetics, Saint Louis University Hospital, St. Louis, MO, 63104, USA; 5) Department of Pediatrics, University of California, San Francisco, CA, 94143-2711, USA; 6) Division of Neurogenetics and Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD, USA; 7) Division of Genetics and Genomics, Boston Children's Hospital/Harvard Medical School/Broad Institute of Massachusetts Institute of Technology and Harvard, Boston, Massachusetts; 8) Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, 98101, USA; 9) Paediatric Department, Bundaberg Hospital, Bundaberg, QLD 4670, Queensland, Australia; 10) Department of Ophthalmology, University of California, San Francisco, CA, 94143-2711, USA; 11) Division of Newborn Medicine and Genetics and Genomics, Manton Center for Orphan Disease Research, Harvard Medical School, Boston MA 02115; 12) Division of Diagnostic Imaging & Radiology, Children’s National Health System, 111 Michigan Ave. NW, Washington, DC 20010; 13) Department of Pediatrics and Medicine, Columbia University, New York, NY, 10032, USA; 14) Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD, 20892-1851, USA; 15) NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD, 20892, USA; 16) Department of Pediatrics (Genetics), University of Washington, Seattle, WA, 98195, USA; 17) Department of Neurology, University of Washington, Seattle, WA, 98195, USA; 18) Program in Developmental Biology, Baylor College of Medicine, Houston, TX, 77030, USA; 19) Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, 77030, USA; 20) Department of Neuroscience, Baylor College of Medicine, Houston, TX, 77030, USA; 21) Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX, 77030, USA; 22) Section of Pediatric Surgery, University of Michigan, Ann Arbor, MI, 48109

WDR40 repeats (WDR) are among the most abundant protein domains and protein- protein interaction motifs in eukaryotes. Currently there are 60 WDR containing proteins associated with diseases reported in OMIM. In this study, we have identified 5 probands that have missense de novo variants in an evolutionarily well conserved WDR protein, WDR37. All of the probands exhibit developmental delay, intellectual disability, epilepsy, colobomas, CHARGE syndrome-like facial dysmorphism and cerebellar hypoplasia phenotypes.

Despite the high level of conservation throughout the entire protein across species, there is very little knowledge about the function of WDR37 and its orthologs. In order to gain more insight in WDR37 function we identified the orthologous gene in Drosophila melanogaster, CG12333 (hereafter named wdr37). We generated null alleles for this previously unstudied gene by replacing the coding region of the gene with transcriptional activator GAL4. wdr37 homozygous mutant animals are viable and fertile, without overt morphological phenotypes. Careful analysis of behavioral phenotypes of wdr37 mutants identified that they exhibit bang sensitivity, which is a phenotype associated physiologically and pharmacologically with epilepsy. Additionally, the flies lost their grip during climbing to the walls of vials and during copulation. All the phenotypes associated with wdr37 loss can be rescued by expressing the human reference cDNA, indicating that the gene is functionally conserved between flies and humans. Interestingly the variant cDNAs could not rescue the phenotypes, suggesting that the variants impair the function of the gene.

In summary, we identified five probands that have de novo missense variants that map to a small region of WDR37 and who exhibit overlapping neurological phenotypes. The analysis of the gene in fly model suggests that the gene is functionally conserved across evolution and the variants impair the function of the gene.