Autosomal Recessive Primary Microcephaly (MCPH) and Novel Pathogenic Variants in ASPM and WDR62 Genes
Hilmi Bolat1, Safiye G Sağer2, Ayberk Türkyılmaz3
1Department of Medical Genetics, Balıkesir University Faculty of Medicine, Balıkesir, Turkey.
Introduction:
Autosomal recessive primary microcephaly (MCPH) is a disorder characterized by congenital microcephaly and intellectual disability without extra-central nervous system malformation. MCPH is a disease with heterogeneity in genotype and phenotype. For this reason, it is important to determine the genetic causes and genotype-phenotype relationship in MCPH, which causes lifelong impairment. In this study, we aimed to evaluate the clinical, genetic, and brain imaging findings of cases diagnosed with MCPH.
Methods:
Electroencephalogram and brain magnetic resonance imaging were performed for all cases. We evaluated genetic results of the 39 families including cases with suspected MCPH diagnosis.
Results:
Genetic diagnosis related to MCPH was provided in 11/39 (28.2%) of these families including 13/41 cases (31.7%). Variants of the WDR62 gene were the most common (61.5%) cause, and variants of the ASPM gene were the second most common cause (38.5%). We have found 6 novel variants and 4 previously reported variants in ASPM and WDR62 genes. Main brain imaging findings in our cases were lissencephaly, polymicrogyria, schizencephaly, pachygyria, and cortical dysplasia. Genetic counseling in 2 families whose genetic diagnosis was determined prevented them from having another child with MCPH.
Discussion/Conclusion:
Detection and reporting of novel variants is an important step in eliminating this disorder by providing families with appropriate genetic counseling.
Insights
Autosomal recessive primary microcephaly (MCPH) is a rare genetic disorder. This study identified genetic variants in 28.2% of families, with WDR62 and ASPM genes being the most common causes, aiding genetic counseling.
Area of Science:
- Genetics
- Neurology
- Medical Science
Background:
- Autosomal recessive primary microcephaly (MCPH) is a congenital disorder characterized by a small head circumference and intellectual disability.
- MCPH exhibits significant genetic and phenotypic heterogeneity, necessitating detailed genetic and clinical investigations.
- Understanding the genotype-phenotype relationship in MCPH is crucial for managing this lifelong condition.
Purpose of the Study:
- To investigate the clinical, genetic, and brain imaging findings in individuals diagnosed with MCPH.
- To identify the genetic causes and genotype-phenotype correlations in MCPH patients.
- To evaluate the utility of genetic diagnosis in family planning for MCPH.
Main Methods:
- Clinical evaluation of suspected MCPH cases.
- Brain magnetic resonance imaging (MRI) and electroencephalogram (EEG) were performed.
- Genetic analysis was conducted on 39 families with suspected MCPH.
Main Results:
- Genetic diagnosis was achieved in 11 out of 39 families (28.2%), identifying 13 affected individuals.
- Variants in the WDR62 gene were the most frequent cause (61.5%), followed by ASPM gene variants (38.5%).
- Six novel variants and four previously reported variants in WDR62 and ASPM were identified. Common brain imaging findings included lissencephaly, polymicrogyria, and cortical dysplasia.
Conclusions:
- Genetic diagnosis in MCPH cases, particularly the identification of novel variants, is essential for providing accurate genetic counseling.
- Identifying the genetic basis of MCPH enables families to make informed reproductive decisions, potentially preventing recurrence.
- This study highlights the importance of integrating genetic testing with clinical and neuroimaging data for comprehensive MCPH diagnosis and management.
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