Computational Genomics in the Era of Precision Medicine: Applications to Variant Analysis and Gene Therapy

Wang, Yung-Chun; Wu, Yuchang; Choi, Julie; Allington, Garrett; Zhao, Shujuan; Khanfar, Mariam; Yang, Kuangying; Fu, Po-Ying; Wrubel, Max; Yu, Xiaobing; Mekbib, Kedous Y.; Ocken, Jack; Smith, Hannah; Shohfi, John; Kahle, Kristopher T.; Lu, Qiongshi; Jin, Sheng Chih

doi:10.3390/jpm12020175

Cited by 7 publications

(4 citation statements)

References 145 publications

(157 reference statements)

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“…Inferred LoF variants consisted of stop-gain, stop-loss, frameshift insertions/deletions, canonical splice site and start-loss. LoF and D-Mis mutations were considered ‘damaging’ 197 .…”

Section: Methodsmentioning

confidence: 99%

Dual impact of PTEN mutation on CSF dynamics and cortical networks via the dysregulation of neural precursors and their interneuron descendants

DeSpenza¹,

Kiziltug²,

Allington³

et al. 2023

Preprint

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Expansion of the cerebrospinal fluid (CSF)-filled cerebral ventricles (ventriculomegaly) is the quintessential feature of congenital hydrocephalus (CH) but also seen in autism spectrum disorder (ASD) and several neuropsychiatric diseases. PTEN is frequently mutated in ASD; here, we show PTEN is a bona fide risk gene for the development of ventriculomegaly, including neurosurgically-treated CH. Pten-mutant hydrocephalus is associated with aqueductal stenosis due to the hyperproliferation of periventricular Nkx2.1+ neural precursors (NPCs) and CSF hypersecretion from inflammation-dependent choroid plexus hyperplasia. The hydrocephalic Pten-mutant cortex exhibits ASD-like network dysfunction due to impaired activity of Nkx2.1+ NPC-derived inhibitory interneurons. Raptor deletion or post-natal Everolimus corrects ventriculomegaly, rescues cortical deficits, and increases survival by antagonizing mTORC1-dependent Nkx2.1+ cell pathology. These results implicate a dual impact of PTEN mutation on CSF dynamics and cortical networks via the dysregulation of NPCs and their interneuron descendants. These data identify a non-surgical treatment target for hydrocephalus and have implications for other developmental brain disorders.

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Section: Methodsmentioning

confidence: 99%

Dual impact of PTEN mutation on CSF dynamics and cortical networks via the dysregulation of neural precursors and their interneuron descendants

DeSpenza¹,

Kiziltug²,

Allington³

et al. 2023

Preprint

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“…LoF and D-Mis variants were considered ‘damaging’. Analyses were conducted separately for each class of variant – de novo variants (DNVs), homozygous recessive variants, and rare, heterozygous dominant variants – following previously established analytical methodologies 33,88 . Firstly, DNVs from the Yale cohort were called from all CH parent-offspring trios using the established TrioDeNovo pipeline 90,91 .…”

Section: Methodsmentioning

confidence: 99%

“…87 Variant filtration and analysis were conducted following GATK best practices and consensus workflows. 88 MetaSVM and MPC algorithms were used to predict the deleteriousness of missense variants (D-mis, defined as MetaSVM-deleterious or MPC-score ≥2). 89 Inferred loss-of-function (LoF) variants consisted of stop-gain, stop-loss, frameshift insertions/deletions, canonical splice site and start-loss.…”

Section: Wes and Variant Callingmentioning

confidence: 99%

A novelSMARCC1-mutant BAFopathy implicates epigenetic dysregulation of neural progenitors in hydrocephalus

Singh

Viviano

Allington

et al. 2023

Preprint

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Importance: Hydrocephalus, characterized by cerebral ventriculomegaly, is the most common disorder requiring brain surgery. A few familial forms of congenital hydrocephalus (CH) have been identified, but the cause of most sporadic cases of CH remains elusive. Recent studies have implicated SMARCC1, a component of the BRG1-associated factor (BAF) chromatin remodeling complex, as a candidate CH gene. However, SMARCC1 variants have not been systematically examined in a large patient cohort or conclusively linked with a human syndrome. Moreover, CH-associated SMARCC1 variants have not been functionally validated or mechanistically studied in vivo. Objectives: The aims of this study are to (i) assess the extent to which rare, damaging de novo mutations (DNMs) in SMARCC1 are associated with cerebral ventriculomegaly; (ii) describe the clinical and radiographic phenotypes of SMARCC1-mutated patients; and (iii) assess the pathogenicity and mechanisms of CH-associated SMARCC1 mutations in vivo. Design, setting, and participants: A genetic association study was conducted using whole-exome sequencing from a cohort consisting of 2,697 ventriculomegalic trios, including patients with neurosurgically-treated CH, totaling 8,091 exomes collected over 5 years (2016-2021). Data were analyzed in 2023. A comparison control cohort consisted of 1,798 exomes from unaffected siblings of patients with autism spectrum disorder and their unaffected parents sourced from the Simons simplex consortium. Main outcomes and measures: Gene variants were identified and filtered using stringent, validated criteria. Enrichment tests assessed gene-level variant burden. In silico biophysical modeling estimated the likelihood and extent of the variant impact on protein structure. The effect of a CH-associated SMARCC1 mutation on the human fetal brain transcriptome was assessed by analyzing RNA-sequencing data. Smarcc1 knockdowns and a patient-specific Smarcc1 variant were tested in Xenopus and studied using optical coherence tomography imaging, in situ hybridization, and immunofluorescence microscopy. Results: SMARCC1 surpassed genome-wide significance thresholds in DNM enrichment tests. Six rare protein-altering DNMs, including four loss-of-function mutations and one recurrent canonical splice site mutation (c.1571+1G>A) were detected in unrelated patients. DNMs localized to the highly conserved DNA-interacting SWIRM, Myb-DNA binding, Glu-rich, and Chromo domains of SMARCC1. Patients exhibited developmental delay (DD), aqueductal stenosis, and other structural brain and heart defects. G0 and G1 Smarcc1 Xenopus mutants exhibited aqueductal stenosis and cardiac defects and were rescued by human wild-type SMARCC1 but not a patient-specific SMARCC1 mutant. Hydrocephalic SMARCC1-mutant human fetal brain and Smarcc1-mutant Xenopus brain exhibited a similarly altered expression of key genes linked to midgestational neurogenesis, including the transcription factors NEUROD2 and MAB21L2. Conclusions: SMARCC1 is a bona fide CH risk gene. DNMs in SMARCC1 cause a novel human BAFopathy we term SMARCC1-associated Developmental Dysgenesis Syndrome (SaDDS), characterized by cerebral ventriculomegaly, aqueductal stenosis, DD, and a variety of structural brain or cardiac defects. These data underscore the importance of SMARCC1 and the BAF chromatin remodeling complex for human brain morphogenesis and provide evidence for a neural stem cell paradigm of human CH pathogenesis. These results highlight the utility of trio-based WES for identifying risk genes for congenital structural brain disorders and suggest WES may be a valuable adjunct in the clinical management of CH patients.

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“…With the development of bioinformatics technology, studying the function and regulation mechanism of genes to find drug targets has become the mainstream direction of medical treatment now. 12,13 By means of bioinformatics, we found that genetic changes between different biological states could serve as potential therapeutic measures for DMED. 14,15 In this article, transcriptome data of normal and DMED rats were obtained from gene expression omnibus (GEO; https://www.ncbi.nlm.nih.gov/gds) GSE2457 dataset.…”

Section: Introductionmentioning

confidence: 99%

Identification of hub biomarkers and exploring the roles of immunity, M6A, ferroptosis, or cuproptosis in rats with diabetic erectile dysfunction

et al. 2022

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Background: Currently, patients with diabetic erectile dysfunction (DMED) were not satisfied with the effects of first-line phosphodiesterase type 5 inhibitors (PDE5Is).Hence, this paper was designed to mine hub biomarkers in DMED and explore its potential mechanisms.Methods: Gene expression matrix of DMED was downloaded from the gene expression omnibus (GEO; GSE2457) dataset. The top 20 genes were selected based on the connectivity degrees in protein-protein interaction (PPI) network. Functional enrichment analysis was utilized to reveal DMED-related signaling pathways. We also explored the roles of immunity, m6A, ferroptosis, or cuproptosis in DMED and constructed Sprague Dawley (SD) rats DMED model to verify gene expressions by quantitative real-time polymerase chain reaction (qRT-PCR).Results: Based on the threshold, a total of 122 differently expressed genes (DEGs) were identified in DMED, including 39 up-regulated and 83 down-regulated genes.Functional enrichment analysis implied that these DEGs were significantly enriched in peroxisome proliferator-activated receptors, ferroptosis, hypoxia-inducible factor 1 signaling pathways, and so on. SD rats DMED model was also successfully established by us and validated by intracavernous pressure/mean arterial pressure, Masson's trichrome staining, and immunohistochemical analysis. We further verified the expression of these top 20 genes from the PPI network by qRT-PCR in the SD rats DMED model and finally identified Sparc, Lox, Srebf1, and Mmp3 as hub biomarkers (all p < 0.05). As for immunity and cuproptosis, our analysis indicated that DMED had nothing to do with them (all p > 0.05). Actually, DMED was markedly associated with m6A regulators and ferroptosis. Conclusions:We identified Sparc, Lox, Srebf1, and Mmp3 as potential hub biomarkers in the SD rats DMED model for future drug development and found its significant associations with m6A regulators and ferroptosis, but not with immunity or cuproptosis.

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Computational Genomics in the Era of Precision Medicine: Applications to Variant Analysis and Gene Therapy

Cited by 7 publications

References 145 publications

Dual impact of PTEN mutation on CSF dynamics and cortical networks via the dysregulation of neural precursors and their interneuron descendants

Dual impact of PTEN mutation on CSF dynamics and cortical networks via the dysregulation of neural precursors and their interneuron descendants

A novelSMARCC1-mutant BAFopathy implicates epigenetic dysregulation of neural progenitors in hydrocephalus

Identification of hub biomarkers and exploring the roles of immunity, M6A, ferroptosis, or cuproptosis in rats with diabetic erectile dysfunction

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