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Intragenic homozygous duplication in HEPACAM is associated with megalencephalic leukoencephalopathy with subcortical

Namanpreet Kaur1, Khyati Arora1, Periyasamy Radhakrishnan1

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

Neurogenetics
|January 27, 2024
PubMed

Insights

This study identifies a novel homozygous duplication in the HEPACAM gene, specifically exons 3 and 4, as the cause of megalencephalic leukoencephalopathy with subcortical cysts 2A (MLC2A). This finding expands the known genetic variants associated with this rare neurological disorder.

Area of Science:

  • Genetics
  • Neurology
  • Molecular Biology

Background:

  • HEPACAM gene variants are linked to megalencephalic leukoencephalopathy with subcortical cysts (MLC2A and MLC2B).
  • MLC2A and MLC2B are characterized by macrocephaly, seizures, motor delay, cognitive impairment, ataxia, and spasticity, with distinctive white matter abnormalities and subcortical cysts on MRI.
  • Previously, 45 individuals across 39 families with biallelic or heterozygous HEPACAM variants causing MLC2A and MLC2B have been reported.

Purpose of the Study:

  • To investigate the genetic cause of megalencephalic leukoencephalopathy with subcortical cysts 2A in a 9-year-old male presenting with characteristic neurological and imaging findings.
  • To identify novel variants in the HEPACAM gene that may lead to MLC2A.

Main Methods:

  • Whole-exome sequencing (WES) was performed on the proband.
  • Copy number variation (CNV) analysis was conducted on WES data to detect deletions or duplications.
  • Quantitative PCR (qPCR) was used to validate the identified CNV and assess carrier status in family members.

Main Results:

  • WES did not identify any clinically significant single nucleotide variants.
  • CNV analysis revealed a homozygous duplication of exons 3 and 4 of the HEPACAM gene in the proband.
  • qPCR confirmed the homozygous duplication in the proband and identified carrier status in both parents.

Conclusions:

  • This study reports the first instance of an intragenic duplication in the HEPACAM gene causing megalencephalic leukoencephalopathy with subcortical cysts 2A (MLC2A).
  • The findings highlight the importance of considering copy number variations, particularly intragenic duplications, in the genetic diagnosis of rare neurological disorders like MLC2A.
  • This discovery expands the spectrum of genetic defects associated with HEPACAM-related leukoencephalopathies.
Keywords:
HEPACAMExome sequencingHomozygous duplicationMegalencephalic leukoencephalopathy with subcortical cystsWhite matter abnormalities

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