Autosomal recessive primary microcephaly type 2 associated with a novel WDR62 splicing variant that disrupts the expression of the functional transcript

Haizhu Chen; Ying Zheng; Hua Wu; Naiqing Cai; Guorong Xu; Yi Lin; Jin-Jing Li

doi:10.3389/fneur.2024.1341864

Autosomal recessive primary microcephaly type 2 associated with a novel WDR62 splicing variant that disrupts the expression of the functional transcript

Front Neurol. 2024 Mar 21:15:1341864. doi: 10.3389/fneur.2024.1341864. eCollection 2024.

Authors

Haizhu Chen^#^{1

2}, Ying Zheng^#^{1

2}, Hua Wu^#^{1

2}, Naiqing Cai^{1

2}, Guorong Xu^{1

2}, Yi Lin^{1

2}, Jin-Jing Li^{1

2}

Affiliations

¹ Department of Neurology, Institute of Neurology of First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, China.
² Department of Neurology and Institute of Neurology of First Affiliated Hospital, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.

^# Contributed equally.

Abstract

Background: Autosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental disorder characterized primarily by congenital microcephaly and intellectual disability but without extra-central nervous system malformations. This investigation aimed to elucidate the genetic underpinnings of microcephaly in a patient from a Chinese consanguineous family.

Methods: A comprehensive clinical assessment, including brain magnetic resonance imaging (MRI), electroencephalogram (EEG), and genetic analyses, was conducted to evaluate the patient's condition. Whole-exome sequencing (WES) was employed to identify the causative gene, followed by Sanger sequencing, to confirm the mutation and its segregation within the family. Reverse transcript polymerase chain reaction (RT-PCR) was utilized to detect changes in splicing. Western blot was employed to reveal the difference of protein expression level between the wild-type and mutant WDR62 in vitro.

Results: The patient exhibited classic MCPH symptoms, including microcephaly, recurrent epilepsy, delayed psychomotor development, and intellectual disability. Additionally, asymmetrical limb length was noted as a prominent feature. MRI findings indicated reduced brain volume with cortical malformations, while EEG demonstrated heightened sharp wave activity. A molecular analysis uncovered a novel homozygous variant c.4154-6 C > G in the WDR62 intron, and a functional analysis confirmed the pathogenicity of this mutation, resulting in the formation of an abnormal transcript with premature termination codons.

Conclusion: This study enhances our understanding of the genetic heterogeneity associated with MCPH and highlights the pivotal role of genetic testing in the diagnosing and managing of rare neurodevelopmental disorders. Furthermore, it highlights the potential of emerging genetic therapies in treating conditions such as MCPH2.

Keywords: WDR62 mutation; autosomal recessive primary microcephaly type 2; brain malformation; consanguineous marriage; epilepsy; microcephaly.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was funded by National Natural Science Foundation of China grants (grant no. 82001217 and 82201630). Additionally, the project received funding from the Joint Funds for the innovation of science and Technology, Fujian province (grant no. 2021Y9012). WES (2000.0 RMB), BamHI and XhoI restriction endonuclease regents (500.0 RMB), primers synthesis (400.0RMB), Sanger sequencing associated regents (750.0RMB), and the “Article Processing Fee” were funded by (grant no. 82001217). Nebuiler HiFi DNA assembly master mix (5623.0 RMB), RT supermix (1250.0 RMB), cell culture regents including serum, basal medium and Penicillin streptomycin (3500.0 RMB), DNA extraction Kit (1125.0 RMB)plasmid extraction kit (5600.0) were funded by (grant no. 82201630), and KOD-plus-neo (3000.0 RMB), Anti-flag (3467.12RMB), Anti-Tubublin (433.16 RMB), HRP-conjugated antibody (175.8 RMB) and other regent for WB and Language polishing fees (2058.0 RMB) were funded by (grant no. 2021Y9012).