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Development (Cambridge, England) Jan 2024Lissencephaly is a neurodevelopmental disorder characterized by a loss of brain surface convolutions caused by genetic variants that disrupt neuronal migration. However,...
Lissencephaly is a neurodevelopmental disorder characterized by a loss of brain surface convolutions caused by genetic variants that disrupt neuronal migration. However, the genetic origins of the disorder remain unidentified in nearly one-fifth of people with lissencephaly. Using whole-exome sequencing, we identified a de novo BAIAP2 variant, p.Arg29Trp, in an individual with lissencephaly with a posterior more severe than anterior (P>A) gradient, implicating BAIAP2 as a potential lissencephaly gene. Spatial transcriptome analysis in the developing mouse cortex revealed that Baiap2 is expressed in the cortical plate and intermediate zone in an anterior low to posterior high gradient. We next used in utero electroporation to explore the effects of the Baiap2 variant in the developing mouse cortex. We found that Baiap2 knockdown caused abnormalities in neuronal migration, morphogenesis and differentiation. Expression of the p.Arg29Trp variant failed to rescue the migration defect, suggesting a loss-of-function effect. Mechanistically, the variant interfered with the ability of BAIAP2 to localize to the cell membrane. These results suggest that the functions of BAIAP2 in the cytoskeleton, cell morphogenesis and migration are important for cortical development and for the pathogenesis of lissencephaly in humans.
Topics: Animals; Humans; Mice; Brain; Cell Movement; Cytoskeleton; Lissencephaly; Microtubule-Associated Proteins
PubMed: 38149472
DOI: 10.1242/dev.201912 -
Brain Sciences Nov 2023Lissencephaly (LIS) is a rare neurodevelopmental disorder with severe symptoms caused by abnormal neuronal migration during cortical development. It is caused by both...
Lissencephaly (LIS) is a rare neurodevelopmental disorder with severe symptoms caused by abnormal neuronal migration during cortical development. It is caused by both genetic and non-genetic factors. Despite frequent studies about the cortex, comprehensive elucidation of structural abnormalities and their effects on the white matter is limited. The main objective of this study is to analyze abnormal neuronal migration pathways and white matter fiber organization in LIS1-associated LIS using diffusion MRI (dMRI) tractography. For this purpose, slabs of brain specimens with LIS ( = 3) and age and sex-matched controls ( = 4) were scanned with 3T dMRI. Our high-resolution ex vivo dMRI successfully identified common abnormalities across the samples. The results revealed an abnormal increase in radially oriented subcortical fibers likely associated with radial migration pathways and u-fibers and a decrease in association fibers in all LIS specimens.
PubMed: 38137102
DOI: 10.3390/brainsci13121655 -
Epilepsia Open Apr 2024About 50% of individuals with developmental and epileptic encephalopathies (DEEs) are unsolved following genetic testing. Deep intronic variants, defined as >100 bp...
About 50% of individuals with developmental and epileptic encephalopathies (DEEs) are unsolved following genetic testing. Deep intronic variants, defined as >100 bp from exon-intron junctions, contribute to disease by affecting the splicing of mRNAs in clinically relevant genes. Identifying deep intronic pathogenic variants is challenging and resource intensive, and interpretation is difficult due to limited functional annotations. We aimed to identify deep intronic variants in individuals suspected to have unsolved single gene DEEs. In a research cohort of unsolved cases of DEEs, we searched for children with a DEE syndrome predominantly caused by variants in specific genes in >80% of described cases. We identified two children with Dravet syndrome and one individual with classic lissencephaly. Multiple sequencing and bioinformatics strategies were employed to interrogate intronic regions in SCN1A and PAFAH1B1. A novel de novo deep intronic 12 kb deletion in PAFAH1B1 was identified in the individual with lissencephaly. We showed experimentally that the deletion disrupts mRNA splicing, which results in partial intron retention after exon 2 and disruption of the highly conserved LisH motif. We demonstrate that targeted interrogation of deep intronic regions using multiple genomics technologies, coupled with functional analysis, can reveal hidden causes of unsolved monogenic DEE syndromes. PLAIN LANGUAGE SUMMARY: Deep intronic variants can cause disease by affecting the splicing of mRNAs in clinically relevant genes. A deep intronic deletion that caused abnormal splicing of the PAFAH1B1 gene was identified in a patient with classic lissencephaly. Our findings reinforce that targeted interrogation of deep intronic regions and functional analysis can reveal hidden causes of unsolved epilepsy syndromes.
Topics: Child; Humans; Introns; Classical Lissencephalies and Subcortical Band Heterotopias; Genetic Testing; Mutation; Epilepsies, Myoclonic
PubMed: 38129960
DOI: 10.1002/epi4.12887 -
Clinical and Experimental Pediatrics Jan 2024
PubMed: 38129099
DOI: 10.3345/cep.2023.01095 -
Neurology Perspectives 2023
PubMed: 38124709
DOI: 10.1016/j.neurop.2023.100135 -
Retinal Cases & Brief Reports Dec 2023To describe a case of TUBA1A-associated optic nerve hypoplasia and persistent fetal vasculature.
PURPOSE
To describe a case of TUBA1A-associated optic nerve hypoplasia and persistent fetal vasculature.
METHODS
Observational case report.
RESULTS
A female, full term infant was found to have a Dandy-Walker malformation with cerebellar and brainstem hypoplasia, ventriculomegaly, and lissencephaly. Her ophthalmic exam was notable for persistent fetal vasculature, optic nerve hypoplasia, vitreous hemorrhage, and peripheral retinal non-perfusion. Subsequent genetic testing revealed a TUBA1A genetic variant.
CONCLUSION
Persistent fetal vasculature, peripheral retinal vascular abnormalities, and optic nerve hypoplasia may be associated with TUBA1A variants. These patients should be carefully evaluated with dilated retinal exam and fluorescein angiography to detect retinal perfusion abnormalities requiring treatment.
PubMed: 38109746
DOI: 10.1097/ICB.0000000000001540 -
BioRxiv : the Preprint Server For... Nov 2023NUDC ( nu clear d istribution protein C) is a mitotic protein involved in nuclear migration and cytokinesis across species. Considered a cytoplasmic dynein (henceforth...
UNLABELLED
NUDC ( nu clear d istribution protein C) is a mitotic protein involved in nuclear migration and cytokinesis across species. Considered a cytoplasmic dynein (henceforth dynein) cofactor, NUDC was shown to associate with the dynein motor complex during neuronal migration. NUDC is also expressed in postmitotic vertebrate rod photoreceptors where its function is unknown. Here, we examined the role of NUDC in postmitotic rod photoreceptors by studying the consequences of a conditional NUDC knockout in mouse rods (r ). Loss of NUDC in rods led to complete photoreceptor cell death at six weeks of age. By 3 weeks of age, r function was diminished, and rhodopsin and mitochondria were mislocalized, consistent with dynein inhibition. Levels of outer segment proteins were reduced, but LIS1 (lissencephaly protein 1), a well-characterized dynein cofactor, was unaffected. Transmission electron microscopy revealed ultrastructural defects within the rods of r by 3 weeks of age. We investigated whether NUDC interacts with the actin modulator cofilin 1 (CFL1) and found that in rods, CFL1 is localized in close proximity to NUDC. In addition to its potential role in dynein trafficking within rods, loss of NUDC also resulted in increased levels of phosphorylated CFL1 (pCFL1), which would purportedly prevent depolymerization of actin. Absence of NUDC also induced an inflammatory response in Müller glia and microglia across the neural retina by 3 weeks of age. Taken together, our data illustrate the critical role of NUDC in actin cytoskeletal maintenance and dynein-mediated protein trafficking in a postmitotic rod photoreceptor.
SIGNIFICANCE STATEMENT
Nuclear distribution protein C (NUDC) has been studied extensively as an essential protein for mitotic cell division. In this study, we discovered its expression and role in the postmitotic rod photoreceptor cell. In the absence of NUDC in mouse rods, we detected functional loss, protein mislocalization, and rapid retinal degeneration consistent with dynein inactivation. In the early phase of retinal degeneration, we observed ultrastructural defects and an upregulation of inflammatory markers suggesting additional, dynein-independent functions of NUDC.
PubMed: 38076848
DOI: 10.1101/2023.11.28.568878 -
Prenatal Diagnosis Apr 2024Determine the incremental diagnostic yield of prenatal exome sequencing (pES) over chromosome microarray (CMA) or G-banding karyotype in fetuses with central nervous... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
Determine the incremental diagnostic yield of prenatal exome sequencing (pES) over chromosome microarray (CMA) or G-banding karyotype in fetuses with central nervous system (CNS) abnormalities.
METHODS
Data were collected via electronic searches from January 2010 to April 2022 in MEDLINE, Cochrane, Web of Science and EMBASE. The NHS England prenatal exome cohort was also included. Incremental yield was calculated as a pooled value using a random-effects model.
RESULTS
Thirty studies were included (n = 1583 cases). The incremental yield with pES for any CNS anomaly was 32% [95%CI 27%-36%; I = 72%]. Subgroup analysis revealed apparent incremental yields in; (a) isolated CNS anomalies; 27% [95%CI 19%-34%; I = 74%]; (b) single CNS anomaly; 16% [95% CI 10%-23%; I = 41%]; (c) more than one CNS anomaly; 31% [95% Cl 21%-40%; I = 56%]; and (d) the anatomical subtype with the most optimal yield was Type 1 malformation of cortical development, related to abnormal cell proliferation or apoptosis, incorporating microcephalies, megalencephalies and dysplasia; 40% (22%-57%; I = 68%). The commonest syndromes in isolated cases were Lissencephaly 3 and X-linked hydrocephalus.
CONCLUSIONS
Prenatal exome sequencing provides a high incremental diagnostic yield in fetuses with CNS abnormalities with optimal yields in cases with multiple CNS anomalies, particularly those affecting the midline, posterior fossa and cortex.
Topics: Pregnancy; Female; Humans; Prospective Studies; Hydrocephalus; Nervous System Malformations; Karyotyping; Karyotype; Fetus; Prenatal Diagnosis; Ultrasonography, Prenatal
PubMed: 38054560
DOI: 10.1002/pd.6466 -
AJNR. American Journal of Neuroradiology Dec 2023The current imaging assessment of fetal brain gyrification is performed qualitatively and subjectively using sonography and MR imaging. A few previous studies have...
BACKGROUND AND PURPOSE
The current imaging assessment of fetal brain gyrification is performed qualitatively and subjectively using sonography and MR imaging. A few previous studies have suggested methods for quantification of fetal gyrification based on 3D reconstructed MR imaging, which requires unique data and is time-consuming. In this study, we aimed to develop an automatic pipeline for gyrification assessment based on routinely acquired fetal 2D MR imaging data, to quantify normal changes with gestation, and to measure differences in fetuses with lissencephaly and polymicrogyria compared with controls.
MATERIALS AND METHODS
We included coronal T2-weighted MR imaging data of 162 fetuses retrospectively collected from 2 clinical sites: 134 controls, 12 with lissencephaly, 13 with polymicrogyria, and 3 with suspected lissencephaly based on sonography, yet with normal MR imaging diagnoses. Following brain segmentation, 5 gyrification parameters were calculated separately for each hemisphere on the basis of the area and ratio between the contours of the cerebrum and its convex hull. Seven machine learning classifiers were evaluated to differentiate control fetuses and fetuses with lissencephaly or polymicrogyria.
RESULTS
In control fetuses, all parameters changed significantly with gestational age ( < .05). Compared with controls, fetuses with lissencephaly showed significant reductions in all gyrification parameters ( ≤ .02). Similarly, significant reductions were detected for fetuses with polymicrogyria in several parameters ( ≤ .001). The 3 suspected fetuses showed normal gyrification values, supporting the MR imaging diagnosis. An XGBoost-linear algorithm achieved the best results for classification between fetuses with lissencephaly and control fetuses ( = 32), with an area under the curve of 0.90 and a recall of 0.83. Similarly, a random forest classifier showed the best performance for classification of fetuses with polymicrogyria and control fetuses ( = 33), with an area under the curve of 0.84 and a recall of 0.62.
CONCLUSIONS
This study presents a pipeline for automatic quantification of fetal brain gyrification and provides normal developmental curves from a large cohort. Our method significantly differentiated fetuses with lissencephaly and polymicrogyria, demonstrating lower gyrification values. The method can aid radiologic assessment, highlight fetuses at risk, and may improve early identification of fetuses with cortical malformations.
Topics: Female; Humans; Polymicrogyria; Retrospective Studies; Brain; Magnetic Resonance Imaging; Lissencephaly; Fetus
PubMed: 38050002
DOI: 10.3174/ajnr.A8046 -
Heliyon Nov 2023Subcortical band heterotopia (SBH) is a rare brain developmental malformation caused by deficient neuronal migration during embryogenesis. Published literature on...
INTRODUCTION
Subcortical band heterotopia (SBH) is a rare brain developmental malformation caused by deficient neuronal migration during embryogenesis. Published literature on pediatric SBH cases caused by mutations is limited.
METHODS
The detailed clinical and genetic features of two pediatric SBH with mutations were analyzed. The available literature on mutations was reviewed.
RESULTS
Both patients were girls with varying degrees of developmental delay. Patient 1 was short in stature with peculiar facial features. Patient 2 had an early seizure onset and developed drug-resistant epilepsy. Whole-exome sequencing (WES) revealed two de novo heterozygous variants of (NM_178153.3), including a novel missense variant of c.568A > G (p.K190E) in P1 and a reported nonsense variant of c.814C > T (p.R272*) in P2. We reviewed all the available literature regarding mutations. A total of 153 different mutations have been reported, with the majority of 99 (64.7 %) being missense mutations.
CONCLUSION
Our study expanded the mutational spectrum of , which has important implications for the study of genotype-phenotype correlations. Furthermore, it provided insights to better understand SBH and genetic counseling.
PubMed: 38045215
DOI: 10.1016/j.heliyon.2023.e22323