Curating the gnomAD database: Report of novel variants in the globin‐coding genes and bioinformatics analysis

Scheps, Karen G.; Hasenahuer, Marcia Anahí; Parisi, Gustavo; Targovnik, Héctor M.; Fornasari, María Elisa

doi:10.1002/humu.23925

Cited by 9 publications

(7 citation statements)

References 64 publications

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“…Hypergeometric tests revealed that COAS, CORS and MIXED genes, but not TFs, were significantly protected (p < 0.01) from loss of function structural variation in normal tissues (GNOMAD 59 ) and significantly enriched in Pan-Cancer fitness genes 60 .…”

Section: Resultsmentioning

confidence: 99%

Identification of transcription factor co-regulators that drive prostate cancer progression

Siddappa

Wani

Long

et al. 2020

Sci Rep

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In prostate cancer (PCa), and many other hormone-dependent cancers, there is clear evidence for distorted transcriptional control as disease driver mechanisms. Defining which transcription factor (TF) and coregulators are altered and combine to become oncogenic drivers remains a challenge, in part because of the multitude of TFs and coregulators and the diverse genomic space on which they function. The current study was undertaken to identify which TFs and coregulators are commonly altered in PCa. We generated unique lists of TFs (n = 2662), coactivators (COA; n = 766); corepressors (COR; n = 599); mixed function coregulators (MIXED; n = 511), and to address the challenge of defining how these genes are altered we tested how expression, copy number alterations and mutation status varied across seven prostate cancer (PCa) cohorts (three of localized and four advanced disease). Testing of significant changes was undertaken by bootstrapping approaches and the most significant changes were identified. For one commonly and significantly altered gene were stably knocked-down expression and undertook cell biology experiments and RNA-Seq to identify differentially altered gene networks and their association with PCa progression risks. COAS, CORS, MIXED and TFs all displayed significant down-regulated expression (q.value < 0.1) and correlated with protein expression (r 0.4–0.55). In localized PCa, stringent expression filtering identified commonly altered TFs and coregulator genes, including well-established (e.g. ERG) and underexplored (e.g. PPARGC1A, encodes PGC1α). Reduced PPARGC1A expression significantly associated with worse disease-free survival in two cohorts of localized PCa. Stable PGC1α knockdown in LNCaP cells increased growth rates and invasiveness and RNA-Seq revealed a profound basal impact on gene expression (~ 2300 genes; FDR < 0.05, logFC > 1.5), but only modestly impacted PPARγ responses. GSEA analyses of the PGC1α transcriptome revealed that it significantly altered the AR-dependent transcriptome, and was enriched for epigenetic modifiers. PGC1α-dependent genes were overlapped with PGC1α-ChIP-Seq genes and significantly associated in TCGA with higher grade tumors and worse disease-free survival. These methods and data demonstrate an approach to identify cancer-driver coregulators in cancer, and that PGC1α expression is clinically significant yet underexplored coregulator in aggressive early stage PCa.

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Section: Resultsmentioning

confidence: 99%

Identification of transcription factor co-regulators that drive prostate cancer progression

Siddappa

Wani

Long

et al. 2020

Sci Rep

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“…Otherwise, we launched Mutect2 in ‘tumor-only’ mode. We supplied Mutect2 with gnomAD 2.1.1 23 population frequency data. Next, we tried to eliminate FFPE artifacts using the LearnReadOrientationModel, GetPileupSummaries, and CalculateContamination tools according to the GATK best practice workflow for somatic short variant discovery.…”

Section: Methodsmentioning

confidence: 99%

“…Stage 1: For further analysis, we filtered out somatic variants with a population frequency threshold >0.5%, according to gnomAD 2.1.1. 23 …”

Section: Methodsmentioning

confidence: 99%

“…Stage 1: For further analysis, we filtered out somatic variants with a population frequency threshold >0.5%, according to gnomAD 2.1.1. 23 Stage 2: Variants matching a known variant annotated in ClinVar with a review status of at least two stars 26 were categorized as the designated pathogenicity category given by ClinVar.…”

Section: Variant Calling and Characterizationmentioning

confidence: 99%

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Platinum-based chemotherapy for pancreatic cancer: impact of mutations in the homologous recombination repair and Fanconi anemia genes

et al. 2022

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Background: Mutations in homologous recombination (HR) and Fanconi anemia (FA) genes may predispose to pancreatic cancer (PC) and enable the prediction of sensitivity to platinum-based chemotherapy. FOLFIRINOX is a standard treatment option for non-selected PC patients and could be effective due to undiagnosed DNA repair deficiency. Here, we aimed to determine the frequency of mutations in genes involved in the HR and FA pathways, evaluate their clinical implications, and determine the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) of PC patients treated with platinum. Methods: We performed targeted DNA sequencing of 30 genes ( ABRAXAS1, ATM, ATR, BARD1, BLM, BRCA1, BRCA2, BRIP1, CDKN2A, CHEK1, CHEK2, FANCC, FANCF, FANCG, FANCI, FANCL, FANCM, MRE11A, NBN, PALB2, PTEN, RAD50, RAD51C, RAD51D, RAD52, RAD54B, RBBP8, RINT1, SLX4, and XRCC2) for 543 PC patients. Results: In BRCA/PALB2-mutated patients with advanced PC (33 patients, 6.1%), the PFS and OS were higher for first-line platinum therapy than for non-platinum therapy [PFS: HR = 0.28, 95% confidence interval (CI) = 0.10–0.81, p = 0.02; OS: HR = 0.31, 95% CI = 0.08–1.16, p = 0.08]. Among 93 patients (17.1%) with mutations in other HR/FA genes, no statistically significant difference in PFS and OS was observed between first-line platinum therapy and non-platinum therapy (PFS: HR = 0.83, 95% CI = 0.43–1.62, p = 0.59; OS: HR = 0.58, 95% CI = 0.28–1.22, p = 0.15). For patients with early PC, no prognostic value was observed for BRCA1/2, PALB2, or other HR/FA genes mutations. Moreover, a personal history of breast, ovarian, pancreatic, or prostate cancer was identified as the only independent predictor of the risk of BRCA/PALB2 mutations (HR = 5.83, 95% CI = 2.16–15.73, p < 0.01). Conclusion: Mutations in the BRCA1/2 and PALB2 genes increase the sensitivity of PC to platinum agents. Thus, alterations in these genes in PC patients must be determined prior to anticancer therapy.

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“…The chromosomal location and type of the identified variants were retrieved in UCSC Genome Browser ( Navarro Gonzalez et al, 2021 ) and NCBI dbSNP ( Bhagwat, 2010 ). The MAFs of the variants were screened in several public databases with a large number of human samples, such as 1000 Genome Project ( n = 2504) ( Siva, 2008 ), NHLBI Exome Sequencing Project (GO-ESP) ( n = 6503) ( Amendola et al, 2015 ), The Exome Aggregation Consortium (ExAC) ( n = 60,706) ( Lek et al, 2016 ), gnomAD ( n = 15,708) ( Scheps et al, 2020 ), and NHLBI Trans-Omics for Precision Medicine (TOPMED) ( n = 60,000) ( Taliun et al, 2021 ). The function prediction of these variants was carried out by online software, PolyPhen-2 ( Adzhubei et al, 2010 ), and PROVEAN ( Choi et al, 2012 ).…”

Section: Methodsmentioning

confidence: 99%

A de Novo ZMIZ1 Pathogenic Variant for Neurodevelopmental Disorder With Dysmorphic Facies and Distal Skeletal Anomalies

et al. 2022

Front. Genet.

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Background: Neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies (NEDDFSA) is a rare syndromic disorder characterized by global neurodevelopmental delay, early-onset hypotonia, poor overall growth, poor speech/language ability, and additional common phenotypes such as eye anomalies, joint hypermobility, and skeletal anomalies of the hands and feet. NEDDFSA is caused by heterozygous pathogenic variants in the ZMIZ1 gene on chromosome 10q22.3 with autosomal dominant (AD) mode of inheritance. All the 32 reported cases with variants in ZMIZ1 gene had a genetic background in Caucasian, Hispanic, North African, and Southeastern Asian. Until now, there are no reports of Chinese patients with ZMIZ1 pathogenic variants.Methods: A 5-year-old girl was found to have the characteristic phenotypes of NEDDFSA. Array-Comparative Genomic Hybridization (array-CGH) and whole exome sequencing (WES) were applied for the trio of this female patient. Sanger sequencing was used to verify the selected variants. A comprehensive molecular analysis was carried out by protein structure prediction, evolutionary conservation, motif scanning, tissue-specific expression, and protein interaction network to elucidate pathogenicity of the identified ZMIZ1 variants.Results: The karyotype was 46, XX with no micro-chromosomal abnormalities identified by array-CGH. There were 20 variants detected in the female patient by WES. A de novo heterozygous missense variant (c.2330G > A, p.Gly777Glu, G777E) was identified in the exon 20 of ZMIZ1. No variants of ZMIZ1 were identified in the non-consanguineous parents and her healthy elder sister. It was predicted that G777E was pathogenic and detrimental to the spatial conformation of the MIZ/SP-RING zinc finger domain of ZMIZ1.Conclusion: Thus far, only four scientific articles reported deleterious variants in ZMIZ1 and most of the cases were from Western countries. This is the first report about a Chinese patient with ZMIZ1 variant. It will broaden the current knowledge of ZMIZ1 variants and variable clinical presentations for clinicians and genetic counselors.

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Curating the gnomAD database: Report of novel variants in the globin‐coding genes and bioinformatics analysis

Cited by 9 publications

References 64 publications

Identification of transcription factor co-regulators that drive prostate cancer progression

Identification of transcription factor co-regulators that drive prostate cancer progression

Platinum-based chemotherapy for pancreatic cancer: impact of mutations in the homologous recombination repair and Fanconi anemia genes

A de Novo ZMIZ1 Pathogenic Variant for Neurodevelopmental Disorder With Dysmorphic Facies and Distal Skeletal Anomalies

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