دورية أكاديمية
أعرض في EDS

Functional filter for whole-genome sequencing data identifies HHT and stress-associated non-coding SMAD4 polyadenylation site variants >5 kb from coding DNA.

التفاصيل البيبلوغرافية
العنوان: Functional filter for whole-genome sequencing data identifies HHT and stress-associated non-coding SMAD4 polyadenylation site variants >5 kb from coding DNA.
المؤلفون: Xiao S; National Heart and Lung Institute, Imperial College London, W12 ONN London, UK; National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, W2 1NY London, UK. Electronic address: sihao.xiao@bnc.ox.ac.uk., Kai Z; Topgen Biopharm Technology Co. Ltd., Shanghai 201203, China., Murphy D; National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, W2 1NY London, UK; Women's, Children's & Clinical Support (Pharmacy), Imperial College Healthcare NHS Trust, W2 1NY London, UK., Li D; National Heart and Lung Institute, Imperial College London, W12 ONN London, UK; National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, W2 1NY London, UK., Patel D; National Heart and Lung Institute, Imperial College London, W12 ONN London, UK; National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, W2 1NY London, UK., Bielowka AM; National Heart and Lung Institute, Imperial College London, W12 ONN London, UK; National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, W2 1NY London, UK., Bernabeu-Herrero ME; National Heart and Lung Institute, Imperial College London, W12 ONN London, UK; National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, W2 1NY London, UK., Abdulmogith A; National Heart and Lung Institute, Imperial College London, W12 ONN London, UK; National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, W2 1NY London, UK., Mumford AD; School of Cellular and Molecular Medicine, University of Bristol, BS8 1QU Bristol, UK., Westbury SK; School of Cellular and Molecular Medicine, University of Bristol, BS8 1QU Bristol, UK., Aldred MA; Division of Pulmonary, Critical Care, Sleep & Occupational Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Vargesson N; School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, AB25 2ZD Aberdeen, UK., Caulfield MJ; William Harvey Research Institute, Queen Mary University of London, E1 4NS London, UK., Shovlin CL; National Heart and Lung Institute, Imperial College London, W12 ONN London, UK; National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, W2 1NY London, UK; Specialist Medicine, Imperial College Healthcare NHS Trust, W12 OHS London, UK. Electronic address: c.shovlin@imperial.ac.uk.
مؤلفون مشاركون: Genomics England Research Consortium; Genomics England, EC1M 6BQ London, UK.
المصدر: American journal of human genetics [Am J Hum Genet] 2023 Nov 02; Vol. 110 (11), pp. 1903-1918. Date of Electronic Publication: 2023 Oct 09.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Cell Press Country of Publication: United States NLM ID: 0370475 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1537-6605 (Electronic) Linking ISSN: 00029297 NLM ISO Abbreviation: Am J Hum Genet Subsets: MEDLINE
أسماء مطبوعة: Publication: 2008- : [Cambridge, MA] : Cell Press
Original Publication: Baltimore, American Society of Human Genetics.
مواضيع طبية MeSH: Smad4 Protein*/genetics , Telangiectasia, Hereditary Hemorrhagic*/genetics, Humans ; Base Sequence ; DNA ; Leukocytes, Mononuclear/pathology ; Nucleotides ; Polyadenylation/genetics ; RNA ; Whole Genome Sequencing
مستخلص: Despite whole-genome sequencing (WGS), many cases of single-gene disorders remain unsolved, impeding diagnosis and preventative care for people whose disease-causing variants escape detection. Since early WGS data analytic steps prioritize protein-coding sequences, to simultaneously prioritize variants in non-coding regions rich in transcribed and critical regulatory sequences, we developed GROFFFY, an analytic tool that integrates coordinates for regions with experimental evidence of functionality. Applied to WGS data from solved and unsolved hereditary hemorrhagic telangiectasia (HHT) recruits to the 100,000 Genomes Project, GROFFFY-based filtration reduced the mean number of variants/DNA from 4,867,167 to 21,486, without deleting disease-causal variants. In three unsolved cases (two related), GROFFFY identified ultra-rare deletions within the 3' untranslated region (UTR) of the tumor suppressor SMAD4, where germline loss-of-function alleles cause combined HHT and colonic polyposis (MIM: 175050). Sited >5.4 kb distal to coding DNA, the deletions did not modify or generate microRNA binding sites, but instead disrupted the sequence context of the final cleavage and polyadenylation site necessary for protein production: By iFoldRNA, an AAUAAA-adjacent 16-nucleotide deletion brought the cleavage site into inaccessible neighboring secondary structures, while a 4-nucleotide deletion unfolded the downstream RNA polymerase II roadblock. SMAD4 RNA expression differed to control-derived RNA from resting and cycloheximide-stressed peripheral blood mononuclear cells. Patterns predicted the mutational site for an unrelated HHT/polyposis-affected individual, where a complex insertion was subsequently identified. In conclusion, we describe a functional rare variant type that impacts regulatory systems based on RNA polyadenylation. Extension of coding sequence-focused gene panels is required to capture these variants.
Competing Interests: Declaration of interests The authors declare no competing interests.
(Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
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معلومات مُعتمدة: MC_EX_MR/M009203/1 United Kingdom MRC_ Medical Research Council; MC_PC_14089 United Kingdom MRC_ Medical Research Council; MR/M009203/1 United Kingdom MRC_ Medical Research Council; R35 HL140019 United States HL NHLBI NIH HHS
فهرسة مساهمة: Keywords: 3′ untranslated region; CADD score; CPA site; PBMCs; alternate exon use; cleavage and polyadenylation site; combined annotation-dependant depletion score; cycloheximide; hereditary hemorrhagic telangiectasia; peripheral blood mononuclear cells; rare variant
المشرفين على المادة: 9007-49-2 (DNA)
0 (Nucleotides)
63231-63-0 (RNA)
0 (Smad4 Protein)
0 (SMAD4 protein, human)
تواريخ الأحداث: Date Created: 20231010 Date Completed: 20231205 Latest Revision: 20240320
رمز التحديث: 20240320
مُعرف محوري في PubMed: PMC10645545
DOI: 10.1016/j.ajhg.2023.09.005
PMID: 37816352
قاعدة البيانات: MEDLINE
الوصف
تدمد:1537-6605
DOI:10.1016/j.ajhg.2023.09.005