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

Andrea Accogli, Mariasavina Severino, Antonella Riva, Francesca Madia, Ganna Balagura, Michele Iacomino, Barbara Carlini, Simona Baldassari, Thea Giacomini, Carolina Croci, Livia Pisciotta, Tullio Messana, Antonella Boni, Angelo Russo, Leonilda Bilo, Rosa Tonziello, Antonietta Coppola, Alessandro Filla, Oriano Mecarelli, Rosario CasaloneFrancesco Pisani, Raffaele Falsaperla, Silvia Marino, Pasquale Parisi, Alessandro Ferretti, Maurizio Elia, Anna Luchetti, Donatella Milani, Francesca Vanadia, Laura Silvestri, Erika Rebessi, Eliana Parente, Giampaolo Vatti, Maria Margherita Mancardi, Lino Nobili, Valeria Capra, Vincenzo Salpietro, Pasquale Striano, Federico 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.

Original languageEnglish
Pages (from-to)145-152
Number of pages8
Publication statusPublished - Aug 2020


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