The Genetics of Tuberous Sclerosis Complex and Related mTORopathies: Current Understanding and Future Directions

Genes, Год журнала: 2024, Номер 15(3), С. 332 - 332

Опубликована: Март 4, 2024

The mechanistic target of rapamycin (mTOR) pathway serves as a master regulator cell growth, proliferation, and survival. Upregulation the mTOR has been shown to cause malformations cortical development, medically refractory epilepsies, neurodevelopmental disorders, collectively described mTORopathies. Tuberous sclerosis complex (TSC) prototypical mTORopathy. Characterized by development benign tumors in multiple organs, pathogenic variants TSC1 or TSC2 disrupt TSC protein complex, negative pathway. Variants critical domains especially catalytic subunit, correlate with increased disease severity. less crucial exons non-coding regions, well those undetectable conventional testing, may lead milder phenotypes. Despite assumption complete penetrance, expressivity varies within families, certain delay onset neurological effects. Understanding these genotype–phenotype correlations is for effective clinical management. Notably, 15% patients have no mutation identified genetic majority cases postulated be caused somatic TSC1/TSC2 which present diagnostic challenges. Advancements prenatal screening, precision medicine hold promise changing treatment paradigm related Herein, we explore molecular mechanisms other mTORopathies, emphasizing contemporary methods understanding diagnosing condition.

Язык: Английский

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Somatic DNA Variants in Epilepsy Surgery Brain Samples from Patients with Lesional Epilepsy

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(2), С. 815 - 815

Опубликована: Янв. 19, 2025

Epilepsy affects 50 million people worldwide and is drug-resistant in approximately one-third of cases. Even when a structural lesion identified as the epileptogenic focus, understanding underlying genetic causes crucial to guide both counseling treatment decisions. Both somatic germline DNA variants may contribute itself and/or influence severity symptoms. We therefore used whole exome sequencing (WES) search for potentially pathogenic brain samples from children with lesional epilepsy who underwent surgery. WES was performed on 20 paired extracted tissue reference same patient, such leukocytes or fibroblasts. The data were jointly analyzed using GATK Mutect2 identify single nucleotide (SNVs) insertions/deletions (InDels), which subsequently evaluated silico their disease-causing potential MutationTaster2021. known five patients (25%) variant allele frequencies (VAF) ranging 3–35% genes MTOR, TSC2, PIK3CA, FGFR1, PIK3R1 cortical malformations central nervous system (CNS) tumors. Depending VAF, we different methods Sanger sequencing, allele-specific qPCR, targeted ultra-deep (amplicon sequencing) confirm variant. In contrast usually straightforward confirmation variants, validation more challenging because current have limitations sensitivity, specificity, cost-effectiveness. our study, additional candidates VAFs 0.7–7.0% that could not be validated by an orthogonal method. This highlights importance validation, especially those very low frequencies.

Язык: Английский

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Brain somatic mosaicism in epilepsy: Bringing results back to the clinic

Neurobiology of Disease, Год журнала: 2023, Номер 181, С. 106104 - 106104

Опубликована: Март 25, 2023

Over the past decade, there has been tremendous progress in understanding brain somatic mosaicism epilepsy research setting. Access to resected tissue samples from patients with medically refractory undergoing surgery key making these discoveries. In this review, we discuss gap between discoveries setting and bringing results back clinical Current genetic testing mainly uses clinically accessible samples, like blood saliva, can detect inherited de novo germline variants potentially non-brain-limited mosaic that have resulted post-zygotic mutation (also called "somatic mutations"). Methods developed brain-limited using need be further translated validated setting, which will allow post-resection diagnoses. However, obtaining a diagnosis after for focal epilepsy, when are available, is arguably "too late" guide precision management. Emerging methods cerebrospinal fluid (CSF) stereoelectroencephalography (SEEG) electrodes hold promise establishing diagnoses pre-resection without actual tissue. parallel, development of curation rules interpreting pathogenicity variants, unique considerations compared assist accredited laboratories geneticists Returning their families end diagnostic odyssey advance

Язык: Английский

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Assessment of gene–disease associations and recommendations for genetic testing for somatic variants in vascular anomalies by VASCERN-VASCA

Orphanet Journal of Rare Diseases, Год журнала: 2024, Номер 19(1)

Опубликована: Май 22, 2024

Vascular anomalies caused by somatic (postzygotic) variants are clinically and genetically heterogeneous diseases with overlapping or distinct entities. The genetic knowledge in this field is rapidly growing, testing now part of the diagnostic workup alongside clinical, radiological histopathological data. Nonetheless, access to still limited, there significant heterogeneity across approaches used laboratories, direct consequences on test sensitivity accuracy. clinical utility expected increase progressively improved theragnostics, which will be based information about efficacy safety emerging drugs future molecules. aim study was make recommendations for optimising guiding patients vascular malformations. Physicians lab specialists from 11 multidisciplinary European centres reviewed genes identified date as being involved non-hereditary malformations, evaluated gene-disease associations, made technical aspects identification low-level mosaicism variant interpretation. A core list 24 were selected current practices participating ISSVA classification literature. In total 45 gene-phenotype associations evaluated: 16 considered definitive, strong, 3 moderate, 7 limited no evidence. This work provides a detailed evidence-based view malformations variants. Knowing both relationships strength greatly help laboratories data interpretation eventually diagnosis. reflects state mid-2023 regularly updated VASCERN-VASCA website (VASCERN-VASCA, https://vascern.eu/groupe/vascular-anomalies/ ).

Язык: Английский

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Genetic testing in children enrolled in epilepsy surgery program. A real-life study

European Journal of Paediatric Neurology, Год журнала: 2023, Номер 47, С. 80 - 87

Опубликована: Окт. 5, 2023

Язык: Английский

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Modified Hard Voting Classifier Implementation on MEFV Gene Variants Increases in Silico Tool Performance: A Novel Approach for Small Sample Size

Journal of Intelligent Systems Theory and Applications, Год журнала: 2025, Номер 8(1), С. 35 - 46

Опубликована: Март 13, 2025

Objective: There are a limited number of pathogenic variants known in the MEFV gene. In silico tools fail to classify many gene variants. Therefore, it is essential implement novel approaches. Our goal develop new strategy solve even classification problem while improving variant prediction accuracy using small datasets. Material - methods: First, we determined optimal computational for model. We then applied eight distinct ML algorithms on training dataset containing tools. initiated application modified hard voting machine learning algorithms, and validation dataset. Subsequently, implemented comparative analysis between results existing studies. Finally, evaluated protein level ascertainment identify hotspot regions. Results: The ensemble classifier scored an average ROCAUC 88%. method correctly classified all with 82% accuracy, outperforming both soft (75%) (70%) methods. showed that prevalence LP was approximately 2.5 times higher domains compared LB variants(χ2: 13.574, p < 0.001, OR: 2.509 [1.532-4.132]). Conclusion: Considering understanding clinical implications associated mutations, employing approach may improve

Язык: Английский

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Modified Rules for Classification of Variants Associated With Disorders of Somatic Mosaicism

Clinical Genetics, Год журнала: 2024, Номер unknown

Опубликована: Окт. 21, 2024

ABSTRACT Disorders of somatic mosaicism (DoSMs) are rare genetic disorders arising from postzygotic alteration leading to segmental/nonsegmental disease. Current professional guidelines for standardized variant interpretation focus on germline and cancer variants, making them suboptimal DoSM interpretation. The Brain Malformations Variant Curation Expert Panel (BMVCEP) modified existing account brain‐specific mosaicism, but applicability other presentations is limited. At Washington University in St. Louis School Medicine, we have adopted the BMVCEP framework suggested alterations that make it more suitable generalized classification. These modifications include (1) expanding beyond genes associated with brain malformations, (2) introduction a criterion interpret truncating variants at C‐terminus gain function genes, (3) establishment allele fraction (VAF) cutoff applying de novo criteria, (4) demonstration silico prediction tools relevant missense variants. Furthermore, reduce number classified as uncertain. classification considerations propose potential improve accuracy classification, better inform clinical care, may benefit laboratories also conducting testing.

Язык: Английский

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Somatic variant analysis of resected brain tissue in epilepsy surgery patients

Epilepsia, Год журнала: 2024, Номер unknown

Опубликована: Окт. 26, 2024

We studied the distribution of germline and somatic variants in epilepsy surgery patients with (suspected) malformations cortical development (MCD) who underwent between 2015 2020 at University Medical Center Utrecht (the Netherlands) pooled our data four previously published cohort studies. Tissue analysis yielded a pathogenic variant 203 663 (31%) combined cases. In 126 379 (33%) focal dysplasia (FCD) type II cases 23 37 (62%) hemimegalencephaly cases, was identified, mostly involving mTOR signaling pathway. Pathogenic 10 genes were found 48 178 (27%) FCDI/mild MCD/mMCD oligodendroglial hyperplasia cases; 36 these (75%) SLC35A2 variants. Six 69 (9%) without histopathological lesion had (n = 5) or DEPDC5 1). A blood DNA confirmed all tissue, allele frequency (VAF) ~50%. seven 114 (6%) mosaicism detected. More than half VAF < 5%. Further correlation genetic surgical outcomes will improve patient counseling may guide postoperative treatment decisions.

Язык: Английский

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Clinical phenotype of the PIK3R1-related vascular overgrowth syndrome

British Journal of Dermatology, Год журнала: 2024, Номер 191(2), С. 303 - 305

Опубликована: Апрель 16, 2024

Here we report 19 additional patients with PIK3R1 mosaic variants clinical phenotyping, showing that the phenotype is indistinguishable from PIK3CA-related phenotypes, although megalencephaly-capillary malformation consistently absent in variants. We also novel consider meaning of PROS should shift ‘PIK3CA-related overgrowth spectrum’ to ‘PI3-kinase-related spectrum’.

Язык: Английский

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Evaluation of Bayesian Point-Based System on the Variant Classification of Hereditary Cancer Predisposition Genes

Genetics in Medicine, Год журнала: 2024, Номер 26(12), С. 101276 - 101276

Опубликована: Сен. 19, 2024

Язык: Английский

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