Targeted re-sequencing in malformations of cortical development: genotype-phenotype correlations

A. Accogli, M. Severino, A. Riva, F. Madia, G. Balagura, M. Iacomino, B. Carlini, S. Baldassari, T. Giacomini, C. Croci, L. Pisciotta, T. Messana, A. Boni, A. Russo, L. Bilo, R. Tonziello, A. Coppola, A. Filla, O. Mecarelli, R. CasaloneF. Pisani, R. Falsaperla, S. Marino, P. Parisi, A. Ferretti, M. Elia, A. Luchetti, D. Milani, F. Vanadia, L. Silvestri, E. Rebessi, E. Parente, G. Vatti, M.M. Mancardi, L. Nobili, V. Capra, V. Salpietro, P. Striano, F. Zara

Research output: Contribution to journalArticlepeer-review


Purpose: Malformations of cortical development (MCD) are a phenotypically and genetically heterogeneous group of disorders, for which the diagnostic rate of genetic testing in a clinical setting remains to be clarified. In this study we aimed to assess the diagnostic rate of germline and pathogenic variants using a custom panel in a heterogeneous group of subjects with MCD and explore genotype-phenotype correlations. Methods: A total of 84 subjects with different MCD were enrolled. Genomic DNA was isolated from peripheral blood. Fifty-nine tartget genes were assessed using a custom next-generation sequencing (NGS) panel. Results: Genetic causes were identified in one-fourth of our cohort (21.4 %). Overall, we identified 19 pathogenic or likely pathogenic single-nucleotide variants in 11 genes among 18 subjects, including PAFAH1B1 (LIS1) (n = 3), TUBA1A (n = 3), DYNC1H1 (n = 3), ACTG1 (n = 2), TUBB2B (n = 1), TUBB3 (n = 1), DCX (n = 1), FLNA (n = 1), LAMA2 (n = 1), POMGNT2 (n = 1) and VLDLR (n = 1). The diagnostic yield was higher in patients with lissencephaly/pachygyria (60 %) (p = 0.001), cobblestone malformation (50 %), and subcortical band heterotopia (SBH) (40 %). Furthermore, five out of six subjects with suspect tubulinopathies on imaging harboured pathogenic variants in tubulin genes. Overall, germline pathogenic variants were more likely to be identified if MCD were diffuse (p = 0.002) and associated with other central nervous system malformations (p = 0.029). Moderate to severe intellectual disability was also more commonly associated with pathogenic variants (p = 0.044). Conclusion: Customized gene panels may support the diagnostic work-up for some specific MCD, especially when these are diffuse, bilateral and associated with other brain malformations. © 2020 British Epilepsy Association
Original languageEnglish
Pages (from-to)145-152
Number of pages8
Publication statusPublished - 2020


  • Brain MRI
  • Gene panel
  • Malformations of cortical development
  • Next-generation sequencing
  • genomic DNA
  • tubulin
  • ACTG1 gene
  • agyria
  • Article
  • brain malformation
  • central nervous system malformation
  • child
  • clinical feature
  • cobblestone malformation
  • cohort analysis
  • cortical dysplasia
  • DCX gene
  • disease severity
  • DYNC1H1 gene
  • female
  • FLNA gene
  • gene
  • gene targeting
  • genetic association
  • genetic variation
  • genotype phenotype correlation
  • germline mutation
  • high throughput sequencing
  • human
  • intellectual impairment
  • LAMA2 gene
  • macrogyria
  • major clinical study
  • male
  • neuroimaging
  • PAFAH1B1 gene
  • POMGNT2 gene
  • priority journal
  • prospective study
  • retrospective study
  • risk factor
  • school child
  • sequence analysis
  • single nucleotide polymorphism
  • subcortical heterotopia
  • TUBA1A gene
  • TUBB2B gene
  • TUBB3 gene
  • VLDLR gene


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