The utility of cerebrospinal fluid-derived cell-free DNA in molecular diagnostics for the-related megalencephaly-capillary malformation (MCAP) syndrome: a case report.

in Cold Spring Harbor molecular case studies by Wei-Liang Chen, Emily Pao, James Owens, Ian Glass, Colin Pritchard, Brain H Shirts, Christina Lockwood, Ghayda M Mirzaa

TLDR

  • Scientists used CSF-derived cfDNA to diagnose MCAP syndrome, achieving accurate results despite limited lesional tissues. This report highlights the potential of minimally invasive-based molecular diagnostic approaches for improved diagnosis and treatment.

Abstract

The megalencephaly-capillary malformation (MCAP) syndrome is an overgrowth disorder caused by mosaic gain-of-function variants inIt is characterized by megalencephaly or hemimegalencephaly, vascular malformations, somatic overgrowth, among other features. Epilepsy is commonly associated with MCAP, and a subset of individuals have cortical malformations requiring resective epilepsy surgery. Like other mosaic disorders, establishing a molecular diagnosis is largely achieved by screening lesional tissues (such as brain or skin), with a low diagnostic yield from peripheral tissues (such as blood). Therefore, in individuals with MCAP in whom lesional tissues are scarce or unavailable or those ineligible for epilepsy surgery, establishing a molecular diagnosis can be challenging. Here we report on the utility of cerebrospinal fluid (CSF)-derived cfDNA for the molecular diagnosis of an individual with MCAP syndrome harboring a mosaicvariant (c.3139C > T, p.His1047Tyr). The proband presented with asymmetric megalencephaly without significant dysgyria. He did not have refractory epilepsy and was therefore not a candidate for epilepsy surgery. However, he developed diffuse large B-cell lymphoma (DLBCL) in late childhood, with four CSF samples obtained via lumbar puncture for cancer staging during which one sample was collected for cfDNA extraction and sequencing.variant allele fractions in CSF cell-free DNA (cfDNA), skin fibroblasts, and peripheral blood were 3.08%, 37.31%, and 2.04%, respectively. This report illustrates the utility of CSF-derived cfDNA in MCAP syndrome. Minimally invasive-based molecular diagnostic approaches utilizing cfDNA not only facilitate accurate genetic diagnosis but also have important therapeutic implications for individuals with refractory epilepsy as repurposed PI3K-AKT-MTOR pathway-inhibitors become more widely available.

Overview

  • The study reports on the use of cerebrospinal fluid (CSF)-derived cell-free DNA (cfDNA) to diagnose megalencephaly-capillary malformation (MCAP) syndrome in an individual who did not have lesional tissues available.
  • The proband presented with asymmetric megalencephaly without significant dysgyria and did not have refractory epilepsy, making him ineligible for epilepsy surgery.
  • The primary objective of the study was to evaluate the utility of CSF-derived cfDNA for molecular diagnosis in individuals with MCAP syndrome.

Comparative Analysis & Findings

  • The variant allele fractions in the CSF (3.08%), skin fibroblasts (37.31%), and peripheral blood (2.04%) were different, highlighting the importance of using CSF-derived cfDNA for molecular diagnosis.
  • The study illustrates the accuracy and therapeutic implications of using minimally invasive-based molecular diagnostic approaches utilizing cfDNA.
  • The findings show the potential for repurposing PI3K-AKT-MTOR pathway-inhibitors as a treatment option for individuals with refractory epilepsy.

Implications and Future Directions

  • The study highlights the potential for CSF-derived cfDNA to improve molecular diagnosis and treatment options for individuals with MCAP syndrome.
  • Future studies could investigate the use of CSF-derived cfDNA for molecular diagnosis in other mosaic disorders.
  • The development of minimally invasive-based molecular diagnostic approaches could lead to earlier diagnosis and potentially improve treatment outcomes for individuals with refractory epilepsy.
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