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Investigation of the most common clinical and imaging findings and the role of tubulin genes in the etiology of malformations of cortical development

ABSTRACT: Background and aim:The number of reports on the role of tubulin gene mutations (TUBA1A, TUBB2B, and TUBB3) in etiology of malformations of cortical development has peaked in recent years. We aimed to determine tubulin gene defects on a patient population with simple and complex malformations of cortical development, and investigate the relationship between tubulin gene mutations and disease phenotype. Materials and methods:We evaluated 47 patients with simple or complex malformations of cortical development, as determined by radiological examination, for demographic features, clinical findings and mutations on TUBA1A, TUBB2B, and TUBB3 genes. Results:According to the magnetic resonance imaging findings, 19 patients (40.5%) had simple malformations of cortical development and 28 (59.5%) patients had complex malformations of cortical development. Focal cortical dysplasia was the most common simple malformation, lissencephaly was the most common coexisting cortical malformation, and corpus callosum anomalies were the most common coexisting extracortical neurodevelopmental abnormalities. None of the patients had genetic alterations on TUBA1A, TUBB2B, and TUBB3 genes causing protein dysfunction. On the other hand, the frequencies of some polymorphisms were higher when compared to the literature. Conclusion:It is crucial to identify the etiology in patients with malformations of cortical development in order to provide appropriate genetic counseling and prenatal diagnosis. We consider that multicenter studies with higher patient numbers and also including other malformations of cortical development-related genes are required to determine underlying etiological factors of malformations of cortical development patients.

SUBMITTER: Aksel Kilicarslan O

PROVIDER: S-EPMC7605093 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Investigation of the most common clinical and imaging findings and the role of tubulin genes in the etiology of malformations of cortical development

Aksel Kiliçarslan Özge Ö Ataman Esra E Gürsoy Semra S Gürbüz Gürkan G Ünalp Aycan A Gençpinar Pinar P Olgaç Dündar Nihal N Edizer Selvinaz S Ülgenalp Ayfer A Giray Bozkaya Özlem Ö

Turkish journal of medical sciences 20201022 6

<h4>Background and aim</h4>The number of reports on the role of tubulin gene mutations (TUBA1A, TUBB2B, and TUBB3) in etiology of malformations of cortical development has peaked in recent years. We aimed to determine tubulin gene defects on a patient population with simple and complex malformations of cortical development, and investigate the relationship between tubulin gene mutations and disease phenotype.<h4>Materials and methods</h4>We evaluated 47 patients with simple or complex malformati ...[more]

PMID: 32718119

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Project description:Post-zygotically acquired genetic variants, or somatic variants, that arise during cortical development have emerged as important causes of focal epilepsies, particularly those due to malformations of cortical development. Pathogenic somatic variants have been identified in many genes within the PI3K-AKT-mTOR-signalling pathway in individuals with hemimegalencephaly and focal cortical dysplasia (type II), and more recently in SLC35A2 in individuals with focal cortical dysplasia (type I) or non-dysplastic epileptic cortex. Given the expanding role of somatic variants across different brain malformations, we sought to delineate the landscape of somatic variants in a large cohort of patients who underwent epilepsy surgery with hemimegalencephaly or focal cortical dysplasia. We evaluated samples from 123 children with hemimegalencephaly (n = 16), focal cortical dysplasia type I and related phenotypes (n = 48), focal cortical dysplasia type II (n = 44), or focal cortical dysplasia type III (n = 15). We performed high-depth exome sequencing in brain tissue-derived DNA from each case and identified somatic single nucleotide, indel and large copy number variants. In 75% of individuals with hemimegalencephaly and 29% with focal cortical dysplasia type II, we identified pathogenic variants in PI3K-AKT-mTOR pathway genes. Four of 48 cases with focal cortical dysplasia type I (8%) had a likely pathogenic variant in SLC35A2. While no other gene had multiple disease-causing somatic variants across the focal cortical dysplasia type I cohort, four individuals in this group had a single pathogenic or likely pathogenic somatic variant in CASK, KRAS, NF1 and NIPBL, genes previously associated with neurodevelopmental disorders. No rare pathogenic or likely pathogenic somatic variants in any neurological disease genes like those identified in the focal cortical dysplasia type I cohort were found in 63 neurologically normal controls (P = 0.017), suggesting a role for these novel variants. We also identified a somatic loss-of-function variant in the known epilepsy gene, PCDH19, present in a small number of alleles in the dysplastic tissue from a female patient with focal cortical dysplasia IIIa with hippocampal sclerosis. In contrast to focal cortical dysplasia type II, neither focal cortical dysplasia type I nor III had somatic variants in genes that converge on a unifying biological pathway, suggesting greater genetic heterogeneity compared to type II. Importantly, we demonstrate that focal cortical dysplasia types I, II and III are associated with somatic gene variants across a broad range of genes, many associated with epilepsy in clinical syndromes caused by germline variants, as well as including some not previously associated with radiographically evident cortical brain malformations.

Dataset Information

Investigation of the most common clinical and imaging findings and the role of tubulin genes in the etiology of malformations of cortical development

Publications

Investigation of the most common clinical and imaging findings and the role of tubulin genes in the etiology of malformations of cortical development

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