Comprehensive genomic analysis of patients with disorders of cerebral cortical development

Wojciech Wiszniewski^{1

2

3}, Pawel Gawlinski⁴, Tomasz Gambin^{4

5}, Monika Bekiesinska-Figatowska⁶, Ewa Obersztyn⁴, Dorota Antczak-Marach⁷, Zeynep Hande Coban Akdemir⁸, Tamar Harel⁸, Ender Karaca⁸, Marta Jurek⁴, Katarzyna Sobecka⁴, Beata Nowakowska⁴, Malgorzata Kruk⁷, Iwona Terczynska⁷, Alicja Goszczanska-Ciuchta⁷, Mariola Rudzka-Dybala⁷, Ewa Jamroz⁹, Antoni Pyrkosz¹⁰, Anna Jakubiuk-Tomaszuk¹¹, Piotr Iwanowski¹², Dorota Gieruszczak-Bialek^{12

13}, Malgorzata Piotrowicz¹⁴, Maria Sasiadek¹⁵, Iwona Kochanowska¹⁶, Barbara Gurda¹⁷, Barbara Steinborn¹⁷, Mateusz Dawidziuk⁴, Jennifer Castaneda⁴, Pawel Wlasienko⁴, Natalia Bezniakow⁴, Shalini N Jhangiani¹⁸, Dorota Hoffman-Zacharska⁴, Jerzy Bal⁴, Elzbieta Szczepanik⁷, Eric Boerwinkle^{18

19}, Richard A Gibbs¹⁸, James R Lupski^{8

18

20

21}

Affiliations

¹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. wiszniew@ohsu.edu.
² Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland. wiszniew@ohsu.edu.
³ Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA. wiszniew@ohsu.edu.
⁴ Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
⁵ Institute of Computer Science, Warsaw University of Technology, Warsaw, Poland.
⁶ Department of Diagnostic Imaging, Institute of Mother and Child, Warsaw, Poland.
⁷ Clinic of Neurology of Children and Adolescents, Institute of Mother and Child, Warsaw, Poland.
⁸ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
⁹ School of Medicine in Katowice, Department of Pediatrics and Developmental Age Neurology, Medical University of Silesia, Katowice, Poland.
¹⁰ Department of Medical Genetics, University of Rzeszow, Rzeszow, Poland.
¹¹ Department of Pediatric Neurology and Rehabilitation, Medical University of Bialystok, Bialystok, Poland.
¹² Department of Medical Genetics, Children's Memorial Health Institute, Warsaw, Poland.
¹³ Department of Pediatrics, Medical University of Warsaw, Warsaw, Poland.
¹⁴ Department of Genetics, Polish Mother's Memorial Hospital - Research Institute, Lodz, Poland.
¹⁵ Department of Genetics, Wroclaw Medical University, Wroclaw, Poland.
¹⁶ Individual Medical Practice in Pediatric Neurology, Szczecin, Poland.
¹⁷ Department of Developmental Neurology, Poznan University of Medical Sciences, Poznan, Poland.
¹⁸ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
¹⁹ Human Genetics Center and Institute of Molecular Medicine, University of Texas-Houston Health Science Center, Houston, TX, USA.
²⁰ Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
²¹ Texas Children's Hospital, Houston, TX, USA.

PMID: 29706646
PMCID: PMC6057976
DOI: 10.1038/s41431-018-0137-z

Comprehensive genomic analysis of patients with disorders of cerebral cortical development

Wojciech Wiszniewski et al. Eur J Hum Genet. 2018 Aug.

. 2018 Aug;26(8):1121-1131.

doi: 10.1038/s41431-018-0137-z. Epub 2018 Apr 30.

Authors

Affiliations

¹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. wiszniew@ohsu.edu.
² Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland. wiszniew@ohsu.edu.
³ Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA. wiszniew@ohsu.edu.
⁴ Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
⁵ Institute of Computer Science, Warsaw University of Technology, Warsaw, Poland.
⁶ Department of Diagnostic Imaging, Institute of Mother and Child, Warsaw, Poland.
⁷ Clinic of Neurology of Children and Adolescents, Institute of Mother and Child, Warsaw, Poland.
⁸ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
⁹ School of Medicine in Katowice, Department of Pediatrics and Developmental Age Neurology, Medical University of Silesia, Katowice, Poland.
¹⁰ Department of Medical Genetics, University of Rzeszow, Rzeszow, Poland.
¹¹ Department of Pediatric Neurology and Rehabilitation, Medical University of Bialystok, Bialystok, Poland.
¹² Department of Medical Genetics, Children's Memorial Health Institute, Warsaw, Poland.
¹³ Department of Pediatrics, Medical University of Warsaw, Warsaw, Poland.
¹⁴ Department of Genetics, Polish Mother's Memorial Hospital - Research Institute, Lodz, Poland.
¹⁵ Department of Genetics, Wroclaw Medical University, Wroclaw, Poland.
¹⁶ Individual Medical Practice in Pediatric Neurology, Szczecin, Poland.
¹⁷ Department of Developmental Neurology, Poznan University of Medical Sciences, Poznan, Poland.
¹⁸ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
¹⁹ Human Genetics Center and Institute of Molecular Medicine, University of Texas-Houston Health Science Center, Houston, TX, USA.
²⁰ Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
²¹ Texas Children's Hospital, Houston, TX, USA.

PMID: 29706646
PMCID: PMC6057976
DOI: 10.1038/s41431-018-0137-z

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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Conflict of interest statement

J.R.L. has stock ownership in 23andMe and Lasergen and is a paid consultant for Regeneron. J.R.L. is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from the chromosomal microarray analysis (CMA) and clinical exome sequencing offered at Baylor Genetics (MGL; http://www.bcm.edu/geneticlabs/). The authors declare that they have no conflict of interest.

Figures

**Fig. 1**
Patient 40689IMID demonstrating a complex brain abnormality due to a synergistic effect of CNV and SNV. Brain imaging studies demonstrated ventriculomegaly (a) that can be explained by *L1CAM* variant, gray matter heterotopia associated with 6q27 deletion (a, b) and brain stem abnormalities (b, c) caused by 15q11 deletion

**Fig. 2**
Segregation analysis of disease-associated variants, facial appearance, and brain imaging studies in patients with disorders of cerebral cortical development. a Patient 16IMID, a compound heterozygote for *CDH4* variants: NM_001794.4: c.[1351G>A]; [2554G>A] (p.(Glu451Lys), p.(Ala852Thr)), demonstrating microcephaly, simplified gyral pattern and dysgenesis of corpus callosum. b Patient 43066IMID, with *ASTN1* NM_004319.2: c.[3283A>C]; [2770C>T], (p.(Met1095Leu), p.(His924Tyr)) variants and diffuse polymicrogyria on brain MRI

See this image and copyright information in PMC

References

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Comprehensive genomic analysis of patients with disorders of cerebral cortical development

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Comprehensive genomic analysis of patients with disorders of cerebral cortical development

Authors

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Abstract

Conflict of interest statement

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