Comprehensive genomic analysis of patients with disorders of cerebral cortical development

Abstract

Malformations of cortical development (MCDs) manifest with structural brain anomalies that lead to neurologic sequelae, including epilepsy, cerebral palsy, developmental delay, and intellectual disability. To investigate the underlying genetic architecture of patients with disorders of cerebral cortical development, a cohort of 54 patients demonstrating neuroradiologic signs of MCDs was investigated. Individual genomes were interrogated for single-nucleotide variants (SNV) and copy number variants (CNV) with whole-exome sequencing and chromosomal microarray studies. Variation affecting known MCDs-associated genes was found in 16/54 cases, including 11 patients with SNV, 2 patients with CNV, and 3 patients with both CNV and SNV, at distinct loci. Diagnostic pathogenic SNV and potentially damaging variants of unknown significance (VUS) were identified in two groups of seven individuals each. We demonstrated that de novo variants are important among patients with MCDs as they were identified in 10/16 individuals with a molecular diagnosis. Three patients showed changes in known MCDs genes and a clinical phenotype beyond the usual characteristics observed, i.e., phenotypic expansion, for a particular known disease gene clinical entity. We also discovered 2 likely candidate genes, CDH4, and ASTN1, with human and animal studies supporting their roles in brain development, and 5 potential candidate genes. Our findings emphasize genetic heterogeneity of MCDs disorders and postulate potential novel candidate genes involved in cerebral cortical development.

Prenatally diagnosed developmental abnormalities of the central nervous system and genetic syndromes: A practical review

“…With the increasing use of new genomic technologies, including chromosomal microarray (CMA) or next generation sequencing for gene‐panel tests and whole genome or exome sequencing (WGS or WES), new genes that cause syndromes and birth defects, especially those involving the brain, are uncovered at an unprecedented pace …”

Clinical variability of TUBB‐associated disorders: Diagnosis through reanalysis

“…Proper microtubules formation is crucial for cellular trafficking, cell migration, and mitosis (M. Breuss & Keays, 2014). Pathogenic mutations in TUBB have previously been implicated in a wide range of syndromes including tubulinopathies, microcephaly, cerebral abnormalities, and Circumferential Skin Creases‐Kunze type (CSC‐KT) (Bahi‐Buisson et al, 2014; M. Breuss & Keays, 2014; Isrie et al, 2015; Kumar et al, 2010; Smith et al, 2014; Wiszniewski et al, 2018). This wide range of phenotypes suggests that TUBB may play a role in the development of several organ systems.…”

“…However, three out of five CSC‐KT patients do not present with any brain abnormalities, in contrast to the three patients with TUBB mutations who presented with microcephaly and structural brain malformations (M. Breuss et al, 2012; Isrie et al, 2015). Recently, the phenotypic range of pathogenic heterozygous mutation carriers has expanded to include cerebral abnormalities (Boissel et al, 2018; Di Donato et al, 2018; Wiszniewski et al, 2018). This suggests that TUBB may have pleiotropic roles in the development of several organ systems.…”

Protective Mechanisms Against DNA Replication Stress in the Nervous System

“…The higher index of variations in these sites of persistent cell proliferation might suggest a correlation between replication stress and the generation of SNVs. Some studies presented associations between these SNVs variations and neurological diseases [365][366][367]. Finally, a lingering question in the field is whether the different examples of genomic mosaicism described in the CNS contribute to the pathogenesis of neurodevelopmental disorders and neurodegenerative diseases.…”