Comprehensive genomic analysis of patients with disorders of cerebral cortical development

Wojciech Wiszniewski, Pawel Gawlinski, Tomasz Gambin, Monika Bekiesinska-Figatowska, Ewa Obersztyn, Dorota Antczak-Marach, Zeynep Hande Coban Akdemir, Tamar Harel, Ender Karaca, Marta Jurek, Katarzyna Sobecka, Beata Nowakowska, Malgorzata Kruk, Iwona Terczynska, Alicja Goszczanska-Ciuchta, Mariola Rudzka-Dybala, Ewa Jamroz, Antoni Pyrkosz, Anna Jakubiuk-Tomaszuk, Piotr Iwanowski & 17 others Dorota Gieruszczak-Bialek, Malgorzata Piotrowicz, Maria Sasiadek, Iwona Kochanowska, Barbara Gurda, Barbara Steinborn, Mateusz Dawidziuk, Jennifer Castaneda, Pawel Wlasienko, Natalia Bezniakow, Shalini N. Jhangiani, Dorota Hoffman-Zacharska, Jerzy Bal, Elzbieta Szczepanik, Eric Boerwinkle, Richard A. Gibbs, James R. Lupski

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1-11
Number of pages11
JournalEuropean Journal of Human Genetics
DOIs
StateAccepted/In press - Apr 30 2018

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Malformations of Cortical Development
Nucleotides
Genes
Exome
Developmental Disabilities
Genetic Heterogeneity
Brain
Cerebral Palsy
Intellectual Disability
Nervous System
Epilepsy
Genome
Phenotype

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Wiszniewski, W., Gawlinski, P., Gambin, T., Bekiesinska-Figatowska, M., Obersztyn, E., Antczak-Marach, D., ... Lupski, J. R. (Accepted/In press). Comprehensive genomic analysis of patients with disorders of cerebral cortical development. European Journal of Human Genetics, 1-11. https://doi.org/10.1038/s41431-018-0137-z

Comprehensive genomic analysis of patients with disorders of cerebral cortical development. / Wiszniewski, Wojciech; Gawlinski, Pawel; Gambin, Tomasz; Bekiesinska-Figatowska, Monika; Obersztyn, Ewa; Antczak-Marach, Dorota; Akdemir, Zeynep Hande Coban; Harel, Tamar; Karaca, Ender; Jurek, Marta; Sobecka, Katarzyna; Nowakowska, Beata; Kruk, Malgorzata; Terczynska, Iwona; Goszczanska-Ciuchta, Alicja; Rudzka-Dybala, Mariola; Jamroz, Ewa; Pyrkosz, Antoni; Jakubiuk-Tomaszuk, Anna; Iwanowski, Piotr; Gieruszczak-Bialek, Dorota; Piotrowicz, Malgorzata; Sasiadek, Maria; Kochanowska, Iwona; Gurda, Barbara; Steinborn, Barbara; Dawidziuk, Mateusz; Castaneda, Jennifer; Wlasienko, Pawel; Bezniakow, Natalia; Jhangiani, Shalini N.; Hoffman-Zacharska, Dorota; Bal, Jerzy; Szczepanik, Elzbieta; Boerwinkle, Eric; Gibbs, Richard A.; Lupski, James R.

In: European Journal of Human Genetics, 30.04.2018, p. 1-11.

Research output: Contribution to journalArticle

Wiszniewski, W, Gawlinski, P, Gambin, T, Bekiesinska-Figatowska, M, Obersztyn, E, Antczak-Marach, D, Akdemir, ZHC, Harel, T, Karaca, E, Jurek, M, Sobecka, K, Nowakowska, B, Kruk, M, Terczynska, I, Goszczanska-Ciuchta, A, Rudzka-Dybala, M, Jamroz, E, Pyrkosz, A, Jakubiuk-Tomaszuk, A, Iwanowski, P, Gieruszczak-Bialek, D, Piotrowicz, M, Sasiadek, M, Kochanowska, I, Gurda, B, Steinborn, B, Dawidziuk, M, Castaneda, J, Wlasienko, P, Bezniakow, N, Jhangiani, SN, Hoffman-Zacharska, D, Bal, J, Szczepanik, E, Boerwinkle, E, Gibbs, RA & Lupski, JR 2018, 'Comprehensive genomic analysis of patients with disorders of cerebral cortical development', European Journal of Human Genetics, pp. 1-11. https://doi.org/10.1038/s41431-018-0137-z
Wiszniewski, Wojciech ; Gawlinski, Pawel ; Gambin, Tomasz ; Bekiesinska-Figatowska, Monika ; Obersztyn, Ewa ; Antczak-Marach, Dorota ; Akdemir, Zeynep Hande Coban ; Harel, Tamar ; Karaca, Ender ; Jurek, Marta ; Sobecka, Katarzyna ; Nowakowska, Beata ; Kruk, Malgorzata ; Terczynska, Iwona ; Goszczanska-Ciuchta, Alicja ; Rudzka-Dybala, Mariola ; Jamroz, Ewa ; Pyrkosz, Antoni ; Jakubiuk-Tomaszuk, Anna ; Iwanowski, Piotr ; Gieruszczak-Bialek, Dorota ; Piotrowicz, Malgorzata ; Sasiadek, Maria ; Kochanowska, Iwona ; Gurda, Barbara ; Steinborn, Barbara ; Dawidziuk, Mateusz ; Castaneda, Jennifer ; Wlasienko, Pawel ; Bezniakow, Natalia ; Jhangiani, Shalini N. ; Hoffman-Zacharska, Dorota ; Bal, Jerzy ; Szczepanik, Elzbieta ; Boerwinkle, Eric ; Gibbs, Richard A. ; Lupski, James R. / Comprehensive genomic analysis of patients with disorders of cerebral cortical development. In: European Journal of Human Genetics. 2018 ; pp. 1-11.
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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.",
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AU - Gawlinski, Pawel

AU - Gambin, Tomasz

AU - Bekiesinska-Figatowska, Monika

AU - Obersztyn, Ewa

AU - Antczak-Marach, Dorota

AU - Akdemir, Zeynep Hande Coban

AU - Harel, Tamar

AU - Karaca, Ender

AU - Jurek, Marta

AU - Sobecka, Katarzyna

AU - Nowakowska, Beata

AU - Kruk, Malgorzata

AU - Terczynska, Iwona

AU - Goszczanska-Ciuchta, Alicja

AU - Rudzka-Dybala, Mariola

AU - Jamroz, Ewa

AU - Pyrkosz, Antoni

AU - Jakubiuk-Tomaszuk, Anna

AU - Iwanowski, Piotr

AU - Gieruszczak-Bialek, Dorota

AU - Piotrowicz, Malgorzata

AU - Sasiadek, Maria

AU - Kochanowska, Iwona

AU - Gurda, Barbara

AU - Steinborn, Barbara

AU - Dawidziuk, Mateusz

AU - Castaneda, Jennifer

AU - Wlasienko, Pawel

AU - Bezniakow, Natalia

AU - Jhangiani, Shalini N.

AU - Hoffman-Zacharska, Dorota

AU - Bal, Jerzy

AU - Szczepanik, Elzbieta

AU - Boerwinkle, Eric

AU - Gibbs, Richard A.

AU - Lupski, James R.

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