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Conference Program

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The Mosaic Mind - Somatic Brain Mosaicism in Neurodevelopmental Disorders and Epilepsy

15 Mar 2024
Venue: Metro Toronto Convention Center
Meeting Room: 718
Clinical Genetics and Therapeutics
  • Accredited:
    • Accredited
  • Primary Categories:
    • Clinical Genetics
  • Secondary Categories:
    • Clinical Genetics
  • Level of Learner:
    • Intermediate
Despite the revolution of exome sequencing, there are many highly heritable conditions without a clear monogenic cause such as Autism Spectrum Disorder (ASD), Intellectual Disability (ID), epilepsy and many neuropsychiatric disorders. One unique type of genetic variants – postzygotic somatic variants (mosaicism) - has just currently identified in the patients with neurodevelopmental disorders. Recent studies have estimated that somatic variants in the probands and in parents transmitted to probands contribute to ASD risk in about 3-5 % of simplex family. Additionally, there is increasing evidence for "brain limited"mosaicism in conditions such as ASD, focal cortical dysplasia (FCD) and hemimegalencephaly (HME). Molecular diagnostics has become more important as the emerging precision medicine (such as pathway-specific inhibitors and genetic therapies) for genetic conditions. In the past decade, deep-sequencing technologies have been developed and widely used. With improved library preparation techniques and better bioinformatics pipelines, fewer alternate allele reads are required to reliably identify single nucleotide variants (SNV) with a low allele frequency. This new development has provided a unique opportunity for accurate diagnosis of somatic brain disorders, which can greatly impact patient management and treatment decisions. In the case of HME and FCD2, caused by somatic variants in PI3K-AKT-MTOR pathway, identifying the underlying molecular cause has become increasingly important, as selective MTOR, AKT3 and PI3K inhibitors, become more widely available. When it comes to diagnosing somatic brain disorders, special consideration must be given to the most appropriate genetic test and tissue or specimen type to ensure the detection of de novo somatic variants. Identifying the underlying molecular cause in most children can only be determined from testing affected (lesional) brain tissues; however, lesional tissue may be difficult to obtain. One potential solution for the tissue availability is the detection of genomic variants from cell-free DNA (cfDNA), which can be extracted from a wide variety of tissues, including cerebrospinal fluid (CSF). Using cfDNA from CSF derived from individuals with brain tumors has been shown to be successful, raising the promise of using this specimen as a "proxy"for molecular diagnosis across a wider range of somatic brain disorders. Recent researches have accurately used deep sequencing of affected brain tissue along with cfDNA from CSF. This approach has the potential to provide a less invasive and more reliable method for diagnosing somatic brain disorders, ultimately leading to more efficient diagnosis and targeted treatment options. Lastly, early recognition and treatment are also crucial for optimal care and outcome for children with epilepsy from neurodevelopmental disorders such as HME and FCD2. These conditions are the most common causes of childhood refractory epilepsy associated with severe neurocognitive comorbidities. In many cases epilepsy surgery may offer a cure or provide significant improvement in seizure control and developmental outcomes. Advances in both genetics and neuroimaging (such as 7T MRI,FDG-PET, SPECT, and functional MRI ) continue to provide us with a better understanding of these disorders and are leading to improvement in medical and surgical therapies.

Learning Objectives

  1. Explain somatic brain mosaicism in autism, intellectual disability, and neuropsychiatric disorders
  2. Identify deep sequencing and CSF cfDNA to detect somatic mosaicism in malformations of cortical development (MCD)
  3. Demonstrate how to clinically assess for brain mosaicism to improve care for children with intractable focal epilepsy
  4. Identify the role of neuroimaging in diagnosis and treatment in FCD and MCD
  5. Describe how genetic testing from SEEG brain samples could improve diagnosis and treatment of disease