TY - JOUR
T1 - Targeted re-sequencing in malformations of cortical development
T2 - genotype-phenotype correlations
AU - Accogli, Andrea
AU - Severino, Mariasavina
AU - Riva, Antonella
AU - Madia, Francesca
AU - Balagura, Ganna
AU - Iacomino, Michele
AU - Carlini, Barbara
AU - Baldassari, Simona
AU - Giacomini, Thea
AU - Croci, Carolina
AU - Pisciotta, Livia
AU - Messana, Tullio
AU - Boni, Antonella
AU - Russo, Angelo
AU - Bilo, Leonilda
AU - Tonziello, Rosa
AU - Coppola, Antonietta
AU - Filla, Alessandro
AU - Mecarelli, Oriano
AU - Casalone, Rosario
AU - Pisani, Francesco
AU - Falsaperla, Raffaele
AU - Marino, Silvia
AU - Parisi, Pasquale
AU - Ferretti, Alessandro
AU - Elia, Maurizio
AU - Luchetti, Anna
AU - Milani, Donatella
AU - Vanadia, Francesca
AU - Silvestri, Laura
AU - Rebessi, Erika
AU - Parente, Eliana
AU - Vatti, Giampaolo
AU - Mancardi, Maria Margherita
AU - Nobili, Lino
AU - Capra, Valeria
AU - Salpietro, Vincenzo
AU - Striano, Pasquale
AU - Zara, Federico
N1 - Copyright © 2020 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
PY - 2020/8
Y1 - 2020/8
N2 - 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.
AB - 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.
U2 - 10.1016/j.seizure.2020.05.023
DO - 10.1016/j.seizure.2020.05.023
M3 - Article
C2 - 32570172
VL - 80
SP - 145
EP - 152
JO - Seizure : the journal of the British Epilepsy Association
JF - Seizure : the journal of the British Epilepsy Association
SN - 1059-1311
ER -