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Intragenic homozygous duplication in HEPACAM is associated with megalencephalic leukoencephalopathy with subcortical cysts type 2A

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Abstract

Disease-causing variants in HEPACAM are associated with megalencephalic leukoencephalopathy with subcortical cysts 2A (MLC2A, MIM# 613,925, autosomal recessive), and megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without impaired intellectual development (MLC2B, MIM# 613,926, autosomal dominant). These disorders are characterised by macrocephaly, seizures, motor delay, cognitive impairment, ataxia, and spasticity. Brain magnetic resonance imaging (MRI) in these individuals shows swollen cerebral hemispheric white matter and subcortical cysts, mainly in the frontal and temporal regions. To date, 45 individuals from 39 families are reported with biallelic and heterozygous variants in HEPACAM, causing MLC2A and MLC2B, respectively. A 9-year-old male presented with developmental delay, gait abnormalities, seizures, macrocephaly, dysarthria, spasticity, and hyperreflexia. MRI revealed subcortical cysts with diffuse cerebral white matter involvement. Whole-exome sequencing (WES) in the proband did not reveal any clinically relevant single nucleotide variants. However, copy number variation analysis from the WES data of the proband revealed a copy number of 4 for exons 3 and 4 of HEPACAM. Validation and segregation were done by quantitative PCR which confirmed the homozygous duplication of these exons in the proband and carrier status in both parents. To the best of our knowledge, this is the first report of an intragenic duplication in HEPACAM causing MLC2A.

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Acknowledgements

We thank the patient and his family for participating in the study. We also thank the National Institutes of Health, USA, for funding the project titled ‘Genetic Diagnosis of Neurodevelopmental Disorders in India’ (1R01HD093570-01A1).

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National Institutes of Health (US),1R01HD093570-01A1,Anju Shukla

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Authors and Affiliations

  1. Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

    Namanpreet Kaur, Khyati Arora, Periyasamy Radhakrishnan, Dhanya Lakshmi Narayanan & Anju Shukla

  2. DBT-Wellcome Trust India Alliance Early Career Clinical and Public Health Research Fellow, Hyderabad, India

    Dhanya Lakshmi Narayanan

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  1. Namanpreet Kaur
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Kaur, N., Arora, K., Radhakrishnan, P. et al. Intragenic homozygous duplication in HEPACAM is associated with megalencephalic leukoencephalopathy with subcortical cysts type 2A. Neurogenetics (2024). https://doi.org/10.1007/s10048-024-00743-1

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