Whole exome sequencing: Uncovering causal genetic variants for ocular diseases

Gupta, Shashank; Chatterjee, Souradip; Mukherjee, Ashim; Mutsuddi, Mousumi

doi:10.1016/j.exer.2017.08.013

Cited by 18 publications

(18 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The technological improvements in analyzing diseases at the genomic, transcriptomic and epigenetic levels allow for the identification of characteristic genetic changes. To detect disease-causing variants (so-called driver mutations) and discover therapeutic target genes, whole exome sequencing (WES) is a highly fruitful sequencing method (1). By applying this method, the coding region of the genome is captured and sequenced at high depth.…”

Section: Introductionmentioning

confidence: 99%

Unraveling the heterogeneous mutational signature of spontaneously developing tumors in MLH1^-/-mice

Gladbach

Wiegele

Hamed

et al. 2019

Preprint

View full text Add to dashboard Cite

28 29 Abbreviations: CMMR-D -constitutional mismatch repair deficiency, cMS -coding 30 microsatellite, MB -Megabase, MMR -mismatch repair, MMR-D -mismatch repair 31 deficiency, TMB -tumor mutational burden, GIT -gastrointestinal tumor, SNV -single 32 nucleotide variant, WES -whole exome sequencing 33 34 Keywords: Tumor mutational burden, exclusive/ shared mutations, predicted tumor antigens Mutations in MLH1 -/tumors 3 35Abstract 36 MLH1 knock out mice represent a preclinical model that resembles features of the human 37 counterpart. As these mice develop mismatch repair deficient (MMR-D) neoplasias in a 38 sequential twin-peaked manner (first lymphomas, then gastrointestinal tumors) we aimed at 39 identification of the underlying molecular mechanisms. Using whole-exome sequencing, we 40 focused on (I) shared and (II) mutually exclusive mutations and described the processes of 41 ongoing mutational events in tumor-derived cultures. 42 A heterogeneous genetic landscape was found, with few mutations shared among different 43 neoplasias (ARID1A and IDH2). Mutations in tumor suppressor genes SMAD4 and POLE 44 were mutually exclusive in lymphomas, most likely contributing to a more aggressive in vivo 45 phenotype. Comparing the mutational profile of selected primary tumors and their 46 corresponding cell line upon in vitro culture revealed continuous increased numbers of 47 somatic gene mutations. The same was true for coding microsatellite mutations in selected 48 MMR-D target genes, showing a gradual increase during in vitro passage. With respect to this 49 latter type of mutations, partial overlap was detectable, yet recognizing shared vaccination 50 antigens. The two most promising candidates are AKT3, a RAC-gamma serine/threonine-51 protein kinase with relevance in maintenance of cellular homeostasis and the endonuclease 52 ERCC5 (Excision Repair 5), involved in DNA excision repair. 53 Novel results of a comparison between spontaneously developing lymphomas and 54 gastrointestinal tumors as models for MMR-D driven tumorigenesis are reported. In addition 55 to identification of ARID1A as a potentially causative mutation hotspot, our comprehensive 56 characterization of the mutational signature is a starting point for immune-based approaches 57 to therapy. 58 59 Mutations in MLH1 -/tumors 4 60 Author Summary 61 This study describes the mutational spectrum of MLH1 -/--associated tumors, spontaneously 62 developing in mice. While these tumors arise at the bottom of the same germline mutation, 63 the clinical presentations as well as resulting molecular alterations are heterogeneous, and 64 thus likely being directly linked. Highly aggressive lymphomas, developing early in life are 65 ultra-hypermutated and harbor mutations in tumor suppressor genes SMAD4 and POLE. 66 Gastrointestinal tumors develop later in life and show different mutations. By performing in-67 depth whole exome sequencing analysis, we here identified for the first time a common 68 mutational hotspot. ARID1A constitutes a potentially causative mutati...

show abstract

Section: Introductionmentioning

confidence: 99%

Unraveling the heterogeneous mutational signature of spontaneously developing tumors in MLH1^-/-mice

Gladbach

Wiegele

Hamed

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…NGS-based panel sequencing of genomic regions of interest has been demonstrated to be a powerful approach for screening of disease-causal variants in clinical applications (Koboldt et al, 2013;Chaitankar et al, 2016;Gupta et al, 2017;Bick et al, 2019). Previously, a predesigned gene panel covering 801 candidate genes for various eye disorders was used successfully to identify the genetic spectra of corneal dystrophies in a Han Chinese population (Zhang et al, 2019c).…”

Section: Introductionmentioning

confidence: 99%

Novel Mutations in COL6A3 That Associated With Peters’ Anomaly Caused Abnormal Intracellular Protein Retention and Decreased Cellular Resistance to Oxidative Stress

Zhang

Dai

et al. 2020

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Peters’ anomaly (PA) is a rare form of anterior segment dysgenesis characterized by central corneal opacity accompanied by iridocorneal or lenticulo-corneal adhesions. Although genetic mutations, particularly those affecting transcription factors that function in eye development, are known to cause PA, the etiology of this disease remains poorly understood. In this study, 23 patients with PA were recruited for panel sequencing. Four out of 23 patients were found to carry variants in known PA causal genes, PITX2 and PITX3. More importantly, two homozygous mutations (NM_057164: p.Val86Ala and p.Arg689Cys) in the COL6A3 gene (collagen type VI alpha-3 chain) that correlated with the phenotype of type I PA were identified, and then validated by following whole-exome sequencing. The expression profile of the COL6A3 gene in the cornea and the impact of the mutations on protein physiological processing and cellular function were further explored. It was shown that COL6A3 presented relatively high expression in the cornea. The mutant COL6A3 protein was relatively retained intracellularly, and its expression reduced cellular resistance to oxidative stress through an enhanced endoplasmic reticulum stress response. Taken together, our findings expanded the known genetic spectrum of PA, and provided evidence for the involvement of COL6A3 or collagen VI in ocular anterior segment development, thereby offering new insight for future investigations targeting PA.

show abstract

“…In recent years, next generation sequencing (NGS) has improved our knowledge about genetic and molecular bases of various spectrums of genetic disorders. With a multilateral vision, NGS, which has rapidly progressed has helped us to find out not only new disease causing variations but also new unreported inheritances, symptoms and has shed light on the way of knowing genetic roles (11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Characterization of a novel pathogenic variation c.1237T>G in the FZD4 gene presenting new inheritance from an Iranian individual suffering vitreoretinopathy

Zamani

Shariati

Seifi

et al. 2020

IRDR

View full text Add to dashboard Cite

Whole exome sequencing: Uncovering causal genetic variants for ocular diseases

Cited by 18 publications

References 50 publications

Unraveling the heterogeneous mutational signature of spontaneously developing tumors in MLH1^-/-mice

Unraveling the heterogeneous mutational signature of spontaneously developing tumors in MLH1^-/-mice

Novel Mutations in COL6A3 That Associated With Peters’ Anomaly Caused Abnormal Intracellular Protein Retention and Decreased Cellular Resistance to Oxidative Stress

Characterization of a novel pathogenic variation c.1237T>G in the FZD4 gene presenting new inheritance from an Iranian individual suffering vitreoretinopathy

Contact Info

Product

Resources

About

Whole exome sequencing: Uncovering causal genetic variants for ocular diseases

Cited by 18 publications

References 50 publications

Unraveling the heterogeneous mutational signature of spontaneously developing tumors in MLH1-/-mice

Unraveling the heterogeneous mutational signature of spontaneously developing tumors in MLH1-/-mice

Novel Mutations in COL6A3 That Associated With Peters’ Anomaly Caused Abnormal Intracellular Protein Retention and Decreased Cellular Resistance to Oxidative Stress

Characterization of a novel pathogenic variation c.1237T>G in the FZD4 gene presenting new inheritance from an Iranian individual suffering vitreoretinopathy

Contact Info

Product

Resources

About

Unraveling the heterogeneous mutational signature of spontaneously developing tumors in MLH1^-/-mice

Unraveling the heterogeneous mutational signature of spontaneously developing tumors in MLH1^-/-mice