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Am J Hum Genet. 2019 Aug 1;105(2):413-424. doi: 10.1016/j.ajhg.2019.06.014. Epub 2019 Jul 18.

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

Collaborators (249)

Acosta MT, Adams DR, Agrawal P, Alejandro ME, Allard P, Alvey J, Andrews A, Ashley EA, Azamian MS, Bacino CA, Bademci G, Baker E, Balasubramanyam A, Baldridge D, Bale J, Barbouth D, Batzli GF, Bayrak-Toydemir P, Beggs AH, Bejerano G, Bellen HJ, Bernstein JA, Berry GT, Bican A, Bick DP, Birch CL, Bivona S, Bohnsack J, Bonnenmann C, Bonner D, Boone BE, Bostwick BL, Botto L, Briere LC, Brokamp E, Brown DM, Brush M, Burke EA, Burrage LC, Butte MJ, Carey J, Carrasquillo O, Chang TCP, Chao HT, Clark GD, Coakley TR, Cobban LA, Cogan JD, Cole FS, Colley HA, Cooper CM, Cope H, Craigen WJ, D'Souza P, Dasari S, Davids M, Dayal JG, Dell'Angelica EC, Dhar SU, Dorrani N, Dorset DC, Douine ED, Draper DD, Duncan L, Eckstein DJ, Emrick LT, Eng CM, Esteves C, Estwick T, Fernandez L, Ferreira C, Fieg EL, Fisher PG, Fogel BL, Forghani I, Fresard L, Gahl WA, Godfrey RA, Goldman AM, Goldstein DB, Gourdine JF, Grajewski A, Groden CA, Gropman AL, Haendel M, Hamid R, Hanchard NA, Hayes N, High F, Holm IA, Hom J, Huang A, Huang Y, Isasi R, Jamal F, Jiang YH, Johnston JM, Jones AL, Karaviti L, Kelley EG, Kiley D, Koeller DM, Kohane IS, Kohler JN, Krakow D, Krasnewich DM, Korrick S, Koziura M, Krier JB, Kyle JE, Lalani SR, Lam B, Lanpher BC, Lanza IR, Lau CC, Lazar J, LeBlanc K, Lee BH, Lee H, Levitt R, Levy SE, Lewis RA, Lincoln SA, Liu P, Liu XZ, Longo N, Loo SK, Loscalzo J, Maas RL, Macnamara EF, MacRae CA, Maduro VV, Majcherska MM, Malicdan MCV, Mamounas LA, Manolio TA, Mao R, Markello TC, Marom R, Marth G, Martin BA, Martin MG, Martínez-Agosto JA, Marwaha S, May T, McCauley J, McConkie-Rosell A, McCormack CE, McCray AT, Metz TO, Might M, Morava-Kozicz E, Moretti PM, Morimoto M, Mulvihill JJ, Murdock DR, Nath A, Nelson SF, Newberry JS, Newman JH, Nicholas SK, Novacic D, Oglesbee D, Orengo JP, Pace L, Pak S, Pallais JC, Palmer CGS, Papp JC, Parker NH, Phillips JA 3rd, Posey JE, Postlethwait JH, Potocki L, Pusey BN, Quinlan A, Raja AN, Renteria G, Reuter CM, Rives L, Robertson AK, Rodan LH, Rosenfeld JA, Rowley RK, Ruzhnikov M, Sacco R, Sampson JB, Samson SL, Saporta M, Schaechter J, Schedl T, Schoch K, Scott DA, Shakachite L, Sharma P, Shashi V, Shields K, Shin J, Signer R, Sillari CH, Silverman EK, Sinsheimer JS, Sisco K, Smith KS, Solnica-Krezel L, Spillmann RC, Stoler JM, Stong N, Sullivan JA, Sutton S, Sweetser DA, Tabor HK, Tamburro CP, Tan QK, Tekin M, Telischi F, Thorson W, Tifft CJ, Toro C, Tran AA, Urv TK, Velinder M, Viskochil D, Vogel TP, Wahl CE, Walley NM, Walsh CA, Walker M, Wambach J, Wan J, Wang LK, Wangler MF, Ward PA, Waters KM, Webb-Robertson BM, Wegner D, Westerfield M, Wheeler MT, Wise AL, Wolfe LA, Woods JD, Worthey EA, Yamamoto S, Yang J, Yoon AJ, Yu G, Zastrow DB, Zhao C, Zuchner S.

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
2
Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, QLD 4029, Australia.
3
Division of Medical Genetics, SSM Health Cardinal Glennon Children's Medical Center, St. Louis, MO 63104, USA; Department of Pediatrics, Saint Louis University Hospital, St. Louis, MO 63104, USA.
4
Department of Pediatrics, University of California, San Francisco, CA 94143-2711, USA.
5
Division of Neurogenetics and Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD 21205, USA.
6
Division of Genetics and Genomics, Boston Children's Hospital/Harvard Medical School/Broad Institute of MIT and Harvard, Boston, MA 02138, USA.
7
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
8
Paediatric Department, Bundaberg Hospital, Bundaberg, QLD 4670, Australia.
9
Department of Ophthalmology, University of California, San Francisco, CA 94143-2711, USA.
10
Division of Newborn Medicine and Genetics and Genomics, Manton Center for Orphan Disease Research, Harvard Medical School, Boston, MA 02115, USA.
11
Division of Diagnostic Imaging & Radiology, Children's National Health System, 111 Michigan Ave. NW, Washington, DC 20010, USA.
12
The Institute of Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia; Murdoch Childrens Research Institute, Melbourne, VIC 3052 Australia.
13
The Institute of Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
14
NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA.
15
Undiagnosed Diseases Network, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD 20892, USA.
16
Department of Pediatrics and Medicine, Columbia University, New York, NY 10032, USA.
17
NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA; Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892-1851, USA.
18
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA; Department of Pediatrics (Genetics), University of Washington, Seattle, WA 98195, USA; Department of Neurology, University of Washington, Seattle, WA 98195, USA.
19
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
20
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
21
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: hbellen@bcm.edu.
22
NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA; Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD 20892-1851, USA. Electronic address: maychristine.malicdan@nih.gov.

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.

KEYWORDS:

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

PMID:
31327508
PMCID:
PMC6699142
[Available on 2020-02-01]
DOI:
10.1016/j.ajhg.2019.06.014

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