De Novo Variants in WDR37 Are Associated with Epilepsy, Colobomas, Dysmorphism, Developmental Delay, Intellectual Disability, and Cerebellar Hypoplasia

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)413-424
Number of pages12
JournalAmerican Journal of Human Genetics
Volume105
Issue number2
DOIs
StatePublished - Aug 1 2019
Externally publishedYes

Bibliographical note

Funding Information:
We thank the probands and their families for participating in this study. We thank Dr. Jessica Tenney and Dr. Balram Gangaram (UCSF) for their inputs on proband 3, and Dr. Jill Madden (The Manton Center, Boston Children's Hospital) for facilitating data collection for proband 5. This paper is supported in part by The Common Fund of the NIH, Office of the Director; NIH NHGRI Intramural Research Grant; NIH grants U54NS093793 to H.J.B. M.F.W. and S.Y.; R24OD022005 and R01GM067858 to H.J.B.; 1F32 NS110174-01 Fellowship award to J.C.A.; Simons Foundation Autism Research Initiative (Award#368479) to M.F.W. and S.Y.; and SFARI and the JPB Foundation (W.K.C). We are thankful for the technical assistance provided by Y. Huang (NIH UDP Translational Laboratory) for Sanger sequencing and Ellen Macnamara for facilitating confirmation of mutation in proband 1. We thank the Bloomington Drosophila Stock Center, Drosophila Genomics and Genetic Resources, and FlyORF for numerous stocks and the Developmental Studies Hybridoma Bank for antibodies. This study made use of data generated by the DECIPHER community; a full list of centers that contributed to the generation of the data is available at https://decipher.sanger.ac.uk and via email at decipher@sanger.ac.uk; funding for the project was provided by the Wellcome Trust. H.J.B. is an investigator of the Howard Hughes Medical Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Funding Information:
We thank the probands and their families for participating in this study. We thank Dr. Jessica Tenney and Dr. Balram Gangaram (UCSF) for their inputs on proband 3, and Dr. Jill Madden (The Manton Center, Boston Children’s Hospital) for facilitating data collection for proband 5. This paper is supported in part by The Common Fund of the NIH, Office of the Director ; NIH NHGRI Intramural Research Grant ; NIH grants U54NS093793 to H.J.B., M.F.W., and S.Y.; R24OD022005 and R01GM067858 to H.J.B.; 1F32 NS110174-01 Fellowship award to J.C.A.; Simons Foundation Autism Research Initiative (Award# 368479 ) to M.F.W. and S.Y.; and SFARI and the JPB Foundation (W.K.C). We are thankful for the technical assistance provided by Y. Huang (NIH UDP Translational Laboratory) for Sanger sequencing and Ellen Macnamara for facilitating confirmation of mutation in proband 1. We thank the Bloomington Drosophila Stock Center, Drosophila Genomics and Genetic Resources, and FlyORF for numerous stocks and the Developmental Studies Hybridoma Bank for antibodies. This study made use of data generated by the DECIPHER community; a full list of centers that contributed to the generation of the data is available at https://decipher.sanger.ac.uk and via email at decipher@sanger.ac.uk ; funding for the project was provided by the Wellcome Trust . H.J.B. is an investigator of the Howard Hughes Medical Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2019

Keywords

  • CG12333
  • Drosophila
  • WD40 repeats
  • WDR37 domains
  • bang sensitivity
  • wdr37

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