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 Casalone; Francesco 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

doi:10.1016/j.seizure.2020.05.023

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

Oasi Research Institute-IRCCS

Research output: Contribution to journal › Article › peer-review

Abstract

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 language	English
Pages (from-to)	145-152
Number of pages	8
Journal	Seizure
Volume	80
DOIs	https://doi.org/10.1016/j.seizure.2020.05.023
Publication status	Published - Aug 2020

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10.1016/j.seizure.2020.05.023

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Accogli, A., Severino, M., Riva, A., Madia, F., Balagura, G., Iacomino, M., Carlini, B., Baldassari, S., Giacomini, T., Croci, C., Pisciotta, L., Messana, T., Boni, A., Russo, A., Bilo, L., Tonziello, R., Coppola, A., Filla, A., Mecarelli, O., ... Zara, F. (2020). Targeted re-sequencing in malformations of cortical development: genotype-phenotype correlations. Seizure, 80, 145-152. https://doi.org/10.1016/j.seizure.2020.05.023

Accogli, A, Severino, M, Riva, A, Madia, F, Balagura, G, Iacomino, M, Carlini, B, Baldassari, S, Giacomini, T, Croci, C, Pisciotta, L, Messana, T, Boni, A, Russo, A, Bilo, L, Tonziello, R, Coppola, A, Filla, A, Mecarelli, O, Casalone, R, Pisani, F, Falsaperla, R, Marino, S, Parisi, P, Ferretti, A, Elia, M, Luchetti, A, Milani, D, Vanadia, F, Silvestri, L, Rebessi, E, Parente, E, Vatti, G, Mancardi, MM, Nobili, L, Capra, V, Salpietro, V, Striano, P & Zara, F 2020, 'Targeted re-sequencing in malformations of cortical development: genotype-phenotype correlations', Seizure, vol. 80, pp. 145-152. https://doi.org/10.1016/j.seizure.2020.05.023

@article{fe7f13f512914c2eaeefd951cfddcc24,

title = "Targeted re-sequencing in malformations of cortical development: genotype-phenotype correlations",

abstract = "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.",

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

year = "2020",

month = aug,

doi = "10.1016/j.seizure.2020.05.023",

language = "English",

volume = "80",

pages = "145--152",

journal = "Seizure : the journal of the British Epilepsy Association",

issn = "1059-1311",

publisher = "W.B. Saunders Ltd",

}

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

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 -

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

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