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Homozygous variant of MLC1 results in megalencephalic leukoencephalopathy with subcortical cysts
Jian Zha1, Yong Chen1, Fangfang Cao1
1Department of Neurology, Jiangxi Provincial Children's Hospital, Nanchang, Jiangxi, China.
Background:
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare, inherited disorder that causes epilepsy, intellectual disorders, and early onset macrocephaly. MLC1 has been identified as a main pathogenic gene.
Methods:
Clinical data such as magnetic resonance imaging (MRI), routine blood tests, and physical examinations were collected from proband. Trio whole-exome sequencing (WES) of the family was performed, and all variants with a minor allele frequency (<0.01) in the exon and canonical splicing sites were selected for further pathogenic evaluation. Candidate variants were validated using Sanger sequencing.
Results:
Here, we report a new homozygous variant identified in two children from the same family in the MLC1 gene [NM_015166.4: c.838_843delinsATTTTA, (p.Ser280_Phe281delinsIleLeu)]. This variant is classified as variant of uncertain significance (VUS) according to the ACMG guidelines. Further experiments demonstrate that the newly identified variant causes a decrease of MLC1 protein levels when expressed in a heterologous expression system.
Conclusion:
Our case expands on this genetic variation and provides new evidence for the clinical diagnosis of MLC1-related MLC.
Insights
A novel variant in the MLC1 gene was identified in two children with megalencephalic leukoencephalopathy with subcortical cysts (MLC). This finding provides new evidence for diagnosing MLC1-related disorders.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare inherited neurological disorder.
- Key features include epilepsy, intellectual disability, and macrocephaly.
- The MLC1 gene is recognized as a primary cause of MLC.
Purpose of the Study:
- To report a novel genetic variant associated with MLC.
- To investigate the pathogenicity of this new variant.
Main Methods:
- Clinical data collection including MRI and genetic testing.
- Trio whole-exome sequencing (WES) was performed.
- Variant validation using Sanger sequencing and functional assays.
Main Results:
- A new homozygous variant (c.838_843delinsATTTTA) in the MLC1 gene was identified in two affected siblings.
- This variant, initially classified as a variant of uncertain significance (VUS), was shown to decrease MLC1 protein levels.
- Functional studies confirmed the variant's impact on protein expression.
Conclusions:
- This case expands the known spectrum of MLC1 genetic variations.
- The findings support the role of this variant in MLC1-related disease.
- Provides crucial evidence for the clinical diagnosis of MLC1-related megalencephalic leukoencephalopathy.
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