Download PDF
J Pediatr Genet 2021; 10(02): 159-163
DOI: 10.1055/s-0040-1712916
Case Report

A Novel Homozygous Frameshift WDR81 Mutation associated with Microlissencephaly, Corpus Callosum Agenesis, and Pontocerebellar Hypoplasia

Tibor Kalmár‡   *
1   Department of Pediatrics, University of Szeged, Szeged, Hungary
,
Katalin Szakszon‡   *
2   Department of Pediatrics, University of Debrecen, Debrecen, Hungary
,
Zoltán Maróti
1   Department of Pediatrics, University of Szeged, Szeged, Hungary
,
Alíz Zimmermann
1   Department of Pediatrics, University of Szeged, Szeged, Hungary
,
Adrienn Máté
1   Department of Pediatrics, University of Szeged, Szeged, Hungary
,
Melinda Zombor
1   Department of Pediatrics, University of Szeged, Szeged, Hungary
,
Csaba Bereczki
1   Department of Pediatrics, University of Szeged, Szeged, Hungary
,
László Sztriha 
1   Department of Pediatrics, University of Szeged, Szeged, Hungary
› Author Affiliations Funding This study was supported by the GINOP-2.3.2-15-2 grant (to T.K. and Z.M.) provided by the National Research, Development and Innovation Office (Hungary).
› Further Information
    Permissions and Reprints

Abstract

Microlissencephaly is a brain malformation characterized by microcephaly and extremely simplified gyral pattern. It may be associated with corpus callosum agenesis and pontocerebellar hypoplasia. In this case report, we described two siblings, a boy and a girl, with this complex brain malformation and lack of any development. In the girl, exome sequencing of a gene set representing 4,813 genes revealed a homozygous AG deletion in exon 7 of the WDR81 gene, leading to a frameshift (c.4668_4669delAG, p.Gly1557AspfsTer16). The parents were heterozygous for this mutation. The boy died without proper genetic testing. Our findings expand the phenotypic and genotypic spectrum of WDR81 gene mutations.

Keywords

microlissencephaly - pontocerebellar hypoplasia - WDR81 mutation

Ethical Approval

Written informed parental consent had been obtained. The study was approved by the Human Investigation Review Board at Albert Szent-Györgyi Clinical Centre, University of Szeged, Hungary.


* Tibor Kalmár and Katalin Szakszon contributed equally to this manuscript.




Publication History

Received: 18 February 2020

Accepted: 22 April 2020

Article published online:
28 May 2020

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Barkovich AJ, Ferriero DM, Barr RM. et al. Microlissencephaly: a heterogeneous malformation of cortical development. Neuropediatrics 1998; 29 (03) 113-119
    Article in Thieme ConnectPubMedGoogle Scholar
  • 2 Alkuraya FS, Cai X, Emery C. et al. Human mutations in NDE1 cause extreme microcephaly with lissencephaly [corrected]. Am J Hum Genet 2011; 88 (05) 536-547
    CrossrefPubMedGoogle Scholar
  • 3 Fallet-Bianco C, Laquerrière A, Poirier K. et al. Mutations in tubulin genes are frequent causes of various foetal malformations of cortical development including microlissencephaly. Acta Neuropathol Commun 2014; 2: 69
    CrossrefPubMedGoogle Scholar
  • 4 Hu WF, Pomp O, Ben-Omran T. et al. Katanin p80 regulates human cortical development by limiting centriole and cilia number. Neuron 2014; 84 (06) 1240-1257
    CrossrefPubMedGoogle Scholar
  • 5 Harding BN, Moccia A, Drunat S. et al. Mutations in citron kinase cause recessive microlissencephaly with multinucleated neurons. Am J Hum Genet 2016; 99 (02) 511-520
    CrossrefPubMedGoogle Scholar
  • 6 Poirier K, Martinovic J, Laquerrière A. et al. Rare ACTG1 variants in fetal microlissencephaly. Eur J Med Genet 2015; 58 (08) 416-418
    CrossrefPubMedGoogle Scholar
  • 7 Cavallin M, Rujano MA, Bednarek N. et al. WDR81 mutations cause extreme microcephaly and impair mitotic progression in human fibroblasts and Drosophila neural stem cells. Brain 2017; 140 (10) 2597-2609
    CrossrefPubMedGoogle Scholar
  • 8 Cappuccio G, Pinelli M, Torella A. et al. An extremely severe phenotype attributed to WDR81 nonsense mutations. Ann Neurol 2017;82:650–651 (Correction). Ann Neurol 2018; 84: 796
    CrossrefPubMedGoogle Scholar
  • 9 Schwarz JM, Cooper DN, Schuelke M, Seelow D. MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods 2014; 11 (04) 361-362
    CrossrefPubMedGoogle Scholar
  • 10 Gulsuner S, Tekinay AB, Doerschner K. et al. Homozygosity mapping and targeted genomic sequencing reveal the gene responsible for cerebellar hypoplasia and quadrupedal locomotion in a consanguineous kindred. Genome Res 2011; 21 (12) 1995-2003
    CrossrefPubMedGoogle Scholar
  • 11 Liu X, Li Y, Wang X. et al. The BEACH-containing protein WDR81 coordinates p62 and LC3C to promote aggrephagy. J Cell Biol 2017; 216 (05) 1301-1320
    CrossrefPubMedGoogle Scholar
  • 12 Shohayeb B, Lim NR, Ho U. et al. The role of WD40-repeat protein 62 (MCPH2) in brain growth: diverse molecular and cellular mechanisms required for cortical development. Mol Neurobiol 2018; 55 (07) 5409-5424
    CrossrefPubMedGoogle Scholar
  • 13 Stirnimann CU, Petsalaki E, Russell RB, Müller CW. WD40 proteins propel cellular networks. Trends Biochem Sci 2010; 35 (10) 565-574
    CrossrefPubMedGoogle Scholar
  • 14 Alazami AM, Patel N, Shamseldin HE. et al. Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families. Cell Reports 2015; 10 (02) 148-161
    CrossrefPubMedGoogle Scholar
  • 15 Shaheen R, Sebai MA, Patel N. et al. The genetic landscape of familial congenital hydrocephalus. Ann Neurol 2017; 81 (06) 890-897
    CrossrefPubMedGoogle Scholar
  • 16 Komara M, John A, Suleiman J, Ali BR, Al-Gazali L. Clinical and molecular delineation of dysequilibrium syndrome type 2 and profound sensorineural hearing loss in an inbred Arab family. Am J Med Genet A 2016; 170A (02) 540-543
    CrossrefPubMedGoogle Scholar
  • 17 Maddirevula S, Alzahrani F, Al-Owain M. et al. Autozygome and high throughput confirmation of disease genes candidacy. Genet Med 2019; 21 (03) 736-742
    CrossrefPubMedGoogle Scholar
  • 18 Traka M, Millen KJ, Collins D. et al. WDR81 is necessary for purkinje and photoreceptor cell survival. J Neurosci 2013; 33 (16) 6834-6844
    CrossrefPubMedGoogle Scholar
  • 19 Liu K, Jian Y, Sun X. et al. Negative regulation of phosphatidylinositol 3-phosphate levels in early-to-late endosome conversion. J Cell Biol 2016; 212 (02) 181-198
    CrossrefPubMedGoogle Scholar
  • 20 Rapiteanu R, Davis LJ, Williamson JC, Timms RT, Paul Luzio J, Lehner PJ. A genetic screen identifies a critical role for the WDR81–WDR91 complex in the trafficking and degradation of tetherin. Traffic 2016; 17 (08) 940-958
    CrossrefPubMedGoogle Scholar