Kanca, O., Andrews, J.C., Lee, P.T., Patel, C., Braddock, S.R., Slavotinek, A.M., Cohen, J.S., Gubbels, C.S., Aldinger, K.A., Williams, J., Indaram, M., Fatemi, A., Yu, T.W., Agrawal, P.B., Vezina, G., Simons, C., Crawford, J., Lau, C.C., Undiagnosed Diseases Network, , Chung, W.K., Markello, T.C., Dobyns, W.B., Adams, D.R., Gahl, W.A., Wangler, M.F., Yamamoto, S., Bellen, H.J., Malicdan, M.C.V. (2019). De Novo Variants in WDR37 Are Associated with Epilepsy, Colobomas, Dysmorphism, Developmental Delay, Intellectual Disability, and Cerebellar Hypoplasia.  Am. J. Hum. Genet. 105(2): 413--424.

FBrf0243068

Research paper

WD40 repeat-containing proteins form a large family of proteins present in all eukaryotes. Here, we identified five pediatric probands with de novo variants in WDR37, which encodes a member of the WD40 repeat protein family. Two probands shared one variant and the others have variants in nearby amino acids outside the WD40 repeats. The probands exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia. The WDR37 protein is highly conserved in vertebrate and invertebrate model organisms and is currently not associated with a human disease. We generated a null allele of the single Drosophila ortholog to gain functional insights and replaced the coding region of the fly gene CG12333/wdr37 with GAL4. These flies are homozygous viable but display severe bang sensitivity, a phenotype associated with seizures in flies. Additionally, the mutant flies fall when climbing the walls of the vials, suggesting a defect in grip strength, and repeat the cycle of climbing and falling. Similar to wall clinging defect, mutant males often lose grip of the female abdomen during copulation. These phenotypes are rescued by using the GAL4 in the CG12333/wdr37 locus to drive the UAS-human reference WDR37 cDNA. The two variants found in three human subjects failed to rescue these phenotypes, suggesting that these alleles severely affect the function of this protein. Taken together, our data suggest that variants in WDR37 underlie a novel syndromic neurological disorder.

PMC6699142 (PMC) (EuropePMC)