Mapping the genomic landscape of inherited retinal disease genes prioritizes genes prone to coding and noncoding copy-number variations

BACKGROUND Array-based comparative genomic hybridization (aCGH) is a reference high-throughput technology for detecting large pathogenic or polymorphic copy-number variations in the human genome; however, a number of quantitative monogenic mutations, such as smaller heterozygous deletions or duplications, are usually missed in most disease genes when proper multiplex ligation-dependent probe assays are not performed. METHODS We developed the Motor Chip, a customized CGH array with exonic coverage of 245 genes involved in neuromuscular disorders (NMDs), as well as 180 candidate disease genes. We analyzed DNA samples from 26 patients with known deletions or duplications in NMDs, 11 patients with partial molecular diagnoses, and 19 patients with a clinical diagnosis alone. RESULTS The Motor Chip efficiently confirmed and refined the copy-number mutations in all of the characterized patients, even when only a single exon was involved. In noncharacterized or partially characterized patients, we found deletions in the SETX (senataxin), SGCG [sarcoglycan, gamma (35kDa dystrophin-associated glycoprotein)], and LAMA2 (laminin, alpha 2) genes, as well as duplications involving LAMA2 and the DYSF [dysferlin, limb girdle muscular dystrophy 2B (autosomal recessive)] locus. CONCLUSIONS The combination of exon-specific gene coverage and optimized platform and probe selection makes the Motor Chip a complementary tool for molecular diagnosis and gene investigation in neuromuscular diseases.

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MON-LB48 The Genomic Landscape of Sporadic Thyrotrophinomas

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.2282 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Angeline shen ◽

Paul Wang ◽

Sunita M C De Sousa ◽

David J Torpy ◽

Hamish Scott ◽

...

Keyword(s):

Cell Adhesion ◽

Rna Polymerase Ii ◽

Copy Number ◽

Large Scale ◽

Neutral Loss ◽

Copy Number Variations ◽

Driver Mutations ◽

Chromosomal Anomalies ◽

Tumour Type ◽

Genomic Landscape

Abstract Background: Thyrotrophinoma (TSHoma) is rare and knowledge on the genomic landscape of this tumour type is very limited. Aim: To perform whole-exome sequencing (WES) in a population of TSHomas to identify recurrent somatic genetic events Method: WES was performed on paired tumour and germline DNA of 7 patients with TSHomas. Three tissue samples were formalin-fixed paraffin-embedded and 4 fresh frozen tumour samples. Fresh blood samples were also collected from each patient. The average of mean depth of coverage amongst all samples was 129X, and 97% of target bases were covered ≥20X. Results:Four (57%) of the seven patients were male and median age at diagnosis was 52 years. (IQR 46, 60) Six patients (86%) had macroadenomas. Four patients (57%) had central thyrotoxicosis at diagnosis and three patients’ tumour stained positive for TSH on histology examination. Two patients (29%) had growth hormone co-secreting tumours. In total, 69 somatic variants were identified to be of potential interest, averaging 1.4 variants per million base-pair of DNA read. No variants were observed in more than one individual. According to the GTEx database, 9 of 69 genes (DRC3, HDAC5, KDM1A, POLR21, TCF25, THAP7, TTC13, UNC5D, UNC13A) were highly expressed in the pituitary (top 10%). Four of these genes appear to contribute to tumour development via epigenetic pathway. Specifically, three of these genes (HDAC5, KDM1A, THAP7) either interact with or form part of histone deacetylases whilst POLR21 encodes a subunit of RNA polymerase II which is responsible for mRNA synthesis. On the other hand, TCF25 gene is thought to act as transcriptional repressor and UNC5D plays a role in cell-cell adhesion. Large scale copy number variations involving gain or loss of whole chromosome or chromosome (chr) arm were observed in six (86%) tumour samples. Chr 5, 9, 13 and 19 were most commonly affected by chromosomal gains. Deletion of chr 1p was seen in two cases and mutations in KDM1A (p.Glu161fs/c.482_491delAGGAAGAAAA) and ADGRB2 gene (p.Leu1565Gln/c.4694T>A) were found in each of the remaining single copy of chr 1p. ADGRB2 gene is thought to be involved in cell adhesion and angiogenesis inhibition. Copy neutral loss-of-heterozygosity were present in two (29%) of the tumour samples (chr 2 and 12q). However, no somatic mutation was found in these regions. Gene level copy number analysis identified a potential deletion in TTI2 gene which encodes for a regulator in DNA damaging response as well as telomere length regulation. ConclusionOverall, the rate of somatic variant mutations in TSHomas is low, consistent with the relative benign nature of this tumour type. No classical driver mutations were identified by this study however, chromosomal anomalies and epigenetics may play an important part in TSHoma development.

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AAV-Txnip prolongs cone survival and vision in mouse models of retinitis pigmentosa

10.1101/2021.01.27.428411 ◽

2021 ◽

Author(s):

Yunlu Xue ◽

Sean K. Wang ◽

Parimal Rana ◽

Emma R. West ◽

Christin M. Hong ◽

...

Keyword(s):

Retinitis Pigmentosa ◽

Mouse Models ◽

Retinal Disease ◽

Disease Genes ◽

Cone Photoreceptors ◽

Adeno Associated Virus ◽

Rescue Effect ◽

Inherited Retinal Disease ◽

High Acuity

AbstractRetinitis pigmentosa (RP) is an inherited retinal disease, affecting >20 million people worldwide. Loss of daylight vision typically occurs due to the dysfunction/loss of cone photoreceptors, the cell type that initiates our color and high acuity vision. Currently, there is no effective treatment for RP, other than gene therapy for a limited number of specific disease genes. To develop a gene-agnostic therapy, we screened ≈20 genes for their ability to prolong cone photoreceptor survival in vivo. Here, we report an adeno-associated virus (AAV) vector expressing Txnip, which prolongs the survival of cone photoreceptors and improves visual acuity in RP mouse models. A Txnip allele, C247S, which blocks the association of Txnip with thioredoxin, provides an even greater benefit. Additionally, the rescue effect of Txnip depends on lactate dehydrogenase b (Ldhb), and correlates with the presence of healthier mitochondria, suggesting that Txnip saves RP cones by enhancing their lactate catabolism.

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Relative contribution of simple mutations vs. copy number variations in five Parkinson disease genes in the Belgian population

Human Mutation ◽

10.1002/humu.21007 ◽

2009 ◽

Vol 30 (7) ◽

pp. 1054-1061 ◽

Cited By ~ 42

Author(s):

Karen Nuytemans ◽

Bram Meeus ◽

David Crosiers ◽

Nathalie Brouwers ◽

Dirk Goossens ◽

...

Keyword(s):

Parkinson Disease ◽

Copy Number ◽

Copy Number Variations ◽

Disease Genes ◽

Relative Contribution ◽

Belgian Population

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The genomic landscape of immune-related genes and its correlations with TMB and PD-L1 expression in Chinese NSCLC.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e21056 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e21056-e21056

Author(s):

Linxin Zheng ◽

Weifeng Li ◽

Wenzhuan Xie ◽

Mengli Huang

Keyword(s):

Copy Number ◽

Small Cell Lung Carcinoma ◽

Immune Therapy ◽

Copy Number Variations ◽

Missense Mutations ◽

Activated T Cells ◽

Cell Lung Carcinoma ◽

Genomic Landscape ◽

Immune Related Genes ◽

Nsclc Patients

e21056 Background: Understanding the genomic landscape of immune-related genes (IRGs) of patient with Non-Small Cell Lung Carcinoma (NSCLC) may provide critical insight and facilitate development of novel strategies for cancer therapy. Methods: Targeted next generation sequencing (NGS) was performed on tissue obtained from patients with NSCLC using a 381-gene panel. The IRGs were mainly based on a published article that summarized the genes related to activated T cells, immune cytolytic activity and IFN-γ release. Genomic alterations including single nucleotide variation (SNV), insertions/deletions, copy number variations (CNV) and gene fusions were assessed. Mutational profiles of IRGs and its correlations with Tumor mutation burden (TMB) and PD-L1 expression in NSCLC patients were analyzed from the 3D Medicine database. Results: Genomic data of 2,510 patients with NSCLC were analyzed via tissue detection [median age 62 years, (IQR: 54 - 69 years)]. 4.26% (107 / 2,510) of the patients had at least one characterized altered IRGs. The most frequently mutated IRGs identified for all genomic alternations occurred in PDCD1LG2 (40%), FAS (27%), LCK (23%), CD274 (21%), CD74 (3%), and missense mutations were the mainly mutant types of PDCD1LG2 and LCK, and copy number gains were showed in PDCD1LG2 and CD274. TMB levels in NSCLC patients with IRGs mutations were higher than in wild-type patients (mean TMB: 14.17 mut/MB vs 9.27 mut/MB, P < 0.001). 65.42% (70/107, 9.35% for PD-L1 > = 1% and < 5%, 28.97% for PD-L1 > = 5% and < 50%, 27.10% for PD-L1 > = 50%) of patients harboring PD-L1-positive ( > = 1%), and the proportion of patients with mutations in IRGs does not exceed 10% in each subgroup. Results of Pearson Chi-square test showed that the PD-L1 expression had different between two groups ( Χ2 = 13.3774, P = 0.0038), patients harboring IRGs mutation had a significantly higher level of PD-L1 than those wide-type patients (P = 0.001). Conclusions: Genomic landscape of IRGs significantly correlated with that of PD-L1 expression. Further analyses using more precisely IRGs and different stage NSCLC samples are requisite to support a role for IRGs as an target to immune therapy of cancers.

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Identification and Analysis of Inherited Retinal Disease Genes

Methods in Molecular Biology - Retinal Degeneration ◽

10.1007/978-1-62703-080-9_1 ◽

2012 ◽

pp. 3-23 ◽

Cited By ~ 11

Author(s):

Kornelia Neveling ◽

Anneke I. den Hollander ◽

Frans P. M. Cremers ◽

Rob W. J. Collin

Keyword(s):

Retinal Disease ◽

Disease Genes ◽

Inherited Retinal Disease

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High-resolution arrays reveal burden of copy number variations on Parkinson disease genes associated with increased disease risk in random cohorts

Neurological Research ◽

10.1080/01616412.2016.1204105 ◽

2016 ◽

Vol 38 (9) ◽

pp. 775-785 ◽

Cited By ~ 1

Author(s):

Megha N. Murthy ◽

Avinash M. Veerappa ◽

Keshava B. Seshachalam ◽

Nallur B. Ramachandra

Keyword(s):

High Resolution ◽

Parkinson Disease ◽

Copy Number ◽

Disease Risk ◽

Copy Number Variations ◽

Disease Genes

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AAV-Txnip prolongs cone survival and vision in mouse models of retinitis pigmentosa

eLife ◽

10.7554/elife.66240 ◽

2021 ◽

Vol 10 ◽

Author(s):

Yunlu Xue ◽

Sean K Wang ◽

Parimal Rana ◽

Emma R West ◽

Christin M Hong ◽

...

Keyword(s):

Retinitis Pigmentosa ◽

Mouse Models ◽

Retinal Disease ◽

Disease Genes ◽

Cone Photoreceptors ◽

Adeno Associated Virus ◽

Rescue Effect ◽

Inherited Retinal Disease ◽

High Acuity

Retinitis pigmentosa (RP) is an inherited retinal disease, affecting >20 million people worldwide. Loss of daylight vision typically occurs due to the dysfunction/loss of cone photoreceptors, the cell type that initiates our color and high acuity vision. Currently, there is no effective treatment for RP, other than gene therapy for a limited number of specific disease genes. To develop a disease gene-agnostic therapy, we screened 20 genes for their ability to prolong cone photoreceptor survival in vivo. Here, we report an adeno-associated virus (AAV) vector expressing Txnip, which prolongs the survival of cone photoreceptors and improves visual acuity in RP mouse models. A Txnip allele, C247S, which blocks the association of Txnip with thioredoxin, provides an even greater benefit. Additionally, the rescue effect of Txnip depends on lactate dehydrogenase b (Ldhb), and correlates with the presence of healthier mitochondria, suggesting that Txnip saves RP cones by enhancing their lactate catabolism.

Download Full-text