Dataset Information

Overlapping cortical malformations in patients with pathogenic variants in GRIN1 and GRIN2B.

ABSTRACT:

Background

Malformations of cortical development (MCDs) have been reported in a subset of patients with pathogenic heterozygous variants in GRIN1 or GRIN2B, genes which encode for subunits of the N-methyl-D-aspartate receptor (NMDAR). The aim of this study was to further define the phenotypic spectrum of NMDAR-related MCDs.

Methods

We report the clinical, radiological and molecular features of 7 new patients and review data on 18 previously reported individuals with NMDAR-related MCDs. Neuropathological findings for two individuals with heterozygous variants in GRIN1 are presented. We report the clinical and neuropathological features of one additional individual with homozygous pathogenic variants in GRIN1.

Results

Heterozygous variants in GRIN1 and GRIN2B were associated with overlapping severe clinical and imaging features, including global developmental delay, epilepsy, diffuse dysgyria, dysmorphic basal ganglia and hippocampi. Neuropathological examination in two fetuses with heterozygous GRIN1 variants suggests that proliferation as well as radial and tangential neuronal migration are impaired. In addition, we show that neuronal migration is also impaired by homozygous GRIN1 variants in an individual with microcephaly with simplified gyral pattern.

Conclusion

These findings expand our understanding of the clinical and imaging features of the 'NMDARopathy' spectrum and contribute to our understanding of the likely underlying pathogenic mechanisms leading to MCD in these patients.

SUBMITTER: Brock S

PROVIDER: S-EPMC10642159 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Publications

Overlapping cortical malformations in patients with pathogenic variants in <i>GRIN1</i> and <i>GRIN2B</i>.

Brock Stefanie S Laquerriere Annie A Marguet Florent F Myers Scott J SJ Hongjie Yuan Y Baralle Diana D Vanderhasselt Tim T Stouffs Katrien K Keymolen Kathelijn K Kim Sukhan S Allen James J Shaulsky Gil G Chelly Jamel J Marcorelle Pascale P Aziza Jacqueline J Villard Laurent L Sacaze Elise E de Wit Marie C Y MCY Wilke Martina M Mancini Grazia Maria Simonetta GMS Hehr Ute U Lim Derek D Mansour Sahar S Mansour Sahar S Traynelis Stephen F SF Beneteau Claire C Denis-Musquer Marie M Jansen Anna C AC Fry Andrew E AE Bahi-Buisson Nadia N

Journal of medical genetics 20220407 2

<h4>Background</h4>Malformations of cortical development (MCDs) have been reported in a subset of patients with pathogenic heterozygous variants in <i>GRIN1</i> or <i>GRIN2B</i>, genes which encode for subunits of the N-methyl-D-aspartate receptor (NMDAR). The aim of this study was to further define the phenotypic spectrum of NMDAR-related MCDs.<h4>Methods</h4>We report the clinical, radiological and molecular features of 7 new patients and review data on 18 previously reported individuals with ...[more]

PMID: 35393335

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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

Overlapping cortical malformations in patients with pathogenic variants in GRIN1 and GRIN2B.

Background

Methods

Results

Conclusion

Publications

Overlapping cortical malformations in patients with pathogenic variants in <i>GRIN1</i> and <i>GRIN2B</i>.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Overlapping cortical malformations in patients with pathogenic variants in GRIN1 and GRIN2B.

Background

Methods

Results

Conclusion

Publications

Overlapping cortical malformations in patients with pathogenic variants in &lt;i&gt;GRIN1&lt;/i&gt; and &lt;i&gt;GRIN2B&lt;/i&gt;.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Overlapping cortical malformations in patients with pathogenic variants in <i>GRIN1</i> and <i>GRIN2B</i>.