Autosomal recessive primary microcephaly type 2 associated with a novel WDR62 splicing variant that disrupts the
Haizhu Chen1,2, Ying Zheng1,2, Hua Wu1,2
1Department of Neurology, Institute of Neurology of First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, China.
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.
Insights
A novel WDR62 gene mutation causes primary microcephaly (MCPH) in a Chinese family. Genetic testing identified a splicing defect, confirming its role in this rare neurodevelopmental disorder.
Area of Science:
- Genetics
- Neuroscience
- Developmental Biology
Background:
- Autosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental disorder.
- Characterized by congenital microcephaly and intellectual disability without other major malformations.
- This study investigated the genetic cause in a Chinese consanguineous family.
Purpose of the Study:
- To identify the genetic basis of microcephaly in a patient from a Chinese consanguineous family.
- To elucidate the role of WDR62 in primary microcephaly.
Main Methods:
- Clinical assessment including MRI and EEG.
- Whole-exome sequencing (WES) to identify gene variants.
- Sanger sequencing, RT-PCR, and Western blot for variant confirmation and functional analysis.
Main Results:
- Patient presented with microcephaly, epilepsy, developmental delay, and intellectual disability.
- Novel homozygous variant c.4154-6 C>G in WDR62 intron identified.
- Functional analysis confirmed pathogenicity, leading to abnormal transcript and premature termination.
Conclusions:
- Enhances understanding of MCPH genetic heterogeneity.
- Highlights the importance of genetic testing for diagnosing rare neurodevelopmental disorders.
- Suggests potential for genetic therapies in conditions like MCPH2.
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