Identification of pathogenic variants in the Brazilian cohort with Familial hypercholesterolemia using exon-targeted gene sequencing

Imagem de Miniatura
Arquivos
art_BORGES_Identification_of_pathogenic_variants_in_the_Brazilian_cohort_2023.PDF (1.37 MB)
Citações na Scopus
1
Tipo de produção
article
Data de publicação
2023
DOI
Scopus
Web of Science
PubMed
Título da Revista
ISSN da Revista
Título do Volume
Editora
ELSEVIER
Autores
BORGES, Jessica Bassani
OLIVEIRA, Victor Fernandes
DAGLI-HERNANDEZ, Carolina
FERREIRA, Glaucio Monteiro
BARBOSA, Thais Kristini Almendros Afonso
MARCAL, Elisangela da Silva Rodrigues
LOS, Bruna
MALAQUIAS, Vanessa Barbosa
BORTOLIN, Raul Hernandes
FREITAS, Renata Caroline Costa
Citação
GENE, v.875, article ID 147501, 10p, 2023
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
Familial hypercholesterolemia (FH) is a monogenic disease characterized by high plasma low-density lipoprotein cholesterol (LDL-c) levels and increased risk of premature atherosclerotic cardiovascular disease. Mutations in FH-related genes account for 40% of FH cases worldwide. In this study, we aimed to assess the pathogenic variants in FH-related genes in the Brazilian FH cohort FHBGEP using exon-targeted gene sequencing (ETGS) strategy. FH patients (n = 210) were enrolled at five clinical sites and peripheral blood samples were obtained for laboratory testing and genomic DNA extraction. ETGS was performed using MiSeq platform (Illumina). To identify deleterious variants in LDLR, APOB, PCSK9, and LDLRAP1, the long-reads were subjected to Burrows -Wheeler Aligner (BWA) for alignment and mapping, followed by variant calling using Genome Analysis Tool -kit (GATK) and ANNOVAR for variant annotation. The variants were further filtered using in-house custom scripts and classified according to the American College Medical Genetics and Genomics (ACMG) guidelines. A total of 174 variants were identified including 85 missense, 3 stop-gain, 9 splice-site, 6 InDel, and 71 in regu-latory regions (3 & PRIME;UTR and 5 & PRIME;UTR). Fifty-two patients (24.7%) had 30 known pathogenic or likely pathogenic variants in FH-related genes according to the American College Medical and Genetics and Genomics guidelines. Fifty-three known variants were classified as benign, or likely benign and 87 known variants have shown un-certain significance. Four novel variants were discovered and classified as such due to their absence in existing databases. In conclusion, ETGS and in silico prediction studies are useful tools for screening deleterious variants and identification of novel variants in FH-related genes, they also contribute to the molecular diagnosis in the FHBGEP cohort.
Palavras-chave
Familial hypercholesterolemia, Exon-targeted gene sequencing, Molecular diagnosis, Single nucleotide variant, Brazilian cohort
URI
https://observatorio.fm.usp.br/handle/OPI/55031
Referências
  1. Allard Delphine, 2005, Hum Mutat, V26, P497, DOI 10.1002/humu.9383
  2. Barbosa TKA, 2023, GENE, V853, DOI 10.1016/j.gene.2022.147084
  3. Alves AC, 2018, ATHEROSCLEROSIS, V277, P448, DOI 10.1016/j.atherosclerosis.2018.06.819
  4. Alves AC, 2014, HUM MOL GENET, V23, P1817, DOI 10.1093/hmg/ddt573
  5. [Anonymous], 1991, BMJ, V303, P893
  6. Araujo JNGD, 2023, GENE, V849, DOI 10.1016/j.gene.2022.146908
  7. Beheshti SO, 2020, J AM COLL CARDIOL, V75, P2553, DOI 10.1016/j.jacc.2020.03.057
  8. Borges JB, 2021, RES SOC ADMIN PHARM, V17, P1347, DOI 10.1016/j.sapharm.2020.10.007
  9. Brnich SE, 2019, GENOME MED, V12, DOI 10.1186/s13073-019-0690-2
  10. Chemello K, 2021, J LIPID RES, V62, DOI 10.1016/j.jlr.2021.100062
  11. Chora JR, 2018, GENET MED, V20, P591, DOI 10.1038/gim.2017.151
  12. Civeira F, 2008, J AM COLL CARDIOL, V52, P1546, DOI 10.1016/j.jacc.2008.06.050
  13. Clarke REJ, 2013, HEART, V99, P175, DOI 10.1136/heartjnl-2012-302917
  14. Coutinho E.R., 2021, ATHEROSCLEROSIS
  15. Izar MCD, 2021, ARQ BRAS CARDIOL, V117, P782, DOI 10.36660/abc.20210788
  16. Silvino JPD, 2020, MOL BIOL REP, V47, P9279, DOI 10.1007/s11033-020-06014-0
  17. Defesche Joep C, 2004, Semin Vasc Med, V4, P59
  18. Defesche JC, 2017, NAT REV DIS PRIMERS, V3, DOI 10.1038/nrdp.2017.93
  19. Di Taranto M.D., 2017, SCI REP-UK, V7, P1
  20. Domanski MJ, 2020, J AM COLL CARDIOL, V76, P1507, DOI 10.1016/j.jacc.2020.07.059
  21. Fasano T, 2009, ATHEROSCLEROSIS, V203, P166, DOI 10.1016/j.atherosclerosis.2008.10.027
  22. Futema M, 2014, J MED GENET, V51, P537, DOI 10.1136/jmedgenet-2014-102405
  23. Futema M, 2012, J MED GENET, V49, P644, DOI 10.1136/jmedgenet-2012-101189
  24. Garg A, 2020, J ENDOCR SOC, V4, DOI 10.1210/jendso/bvz015
  25. Guo QY, 2020, FRONT GENET, V11, DOI 10.3389/fgene.2020.01020
  26. Hegele RA, 2019, CURR OPIN LIPIDOL, V30, P53, DOI 10.1097/MOL.0000000000000579
  27. Henderson R, 2016, J BIOMED SCI, V23, DOI 10.1186/s12929-016-0256-1
  28. Hooper AJ, 2018, CURR ATHEROSCLER REP, V20, DOI 10.1007/s11883-018-0731-0
  29. Hopkins PN, 2015, CIRC-CARDIOVASC GENE, V8, P823, DOI 10.1161/CIRCGENETICS.115.001129
  30. Hovland A, 2022, FRONT GENET, V13, DOI 10.3389/fgene.2022.1072108
  31. Hsiung YC, 2018, ATHEROSCLEROSIS, V277, P440, DOI 10.1016/j.atherosclerosis.2018.08.022
  32. Hu PW, 2020, CIRCULATION, V141, P1742, DOI 10.1161/CIRCULATIONAHA.119.044795
  33. Iacocca MA, 2017, EXPERT REV MOL DIAGN, V17, P641, DOI 10.1080/14737159.2017.1332997
  34. Jannes C.E., 2015, ATHEROSCLEROSIS
  35. Jannes CE, 2022, ARQ BRAS CARDIOL, V118, P669, DOI 10.36660/abc.20201371
  36. Santos PCJL, 2014, ATHEROSCLEROSIS, V233, P206, DOI 10.1016/j.atherosclerosis.2013.12.028
  37. Khera AV, 2016, J AM COLL CARDIOL, V67, P2578, DOI 10.1016/j.jacc.2016.03.520
  38. Koboldt DC, 2020, GENOME MED, V12, DOI 10.1186/s13073-020-00791-w
  39. Lamiquiz-Moneo I, 2018, REV ESP CARDIOL, V71, P351, DOI [10.1016/j.rec.2017.07.010, 10.1016/j.recesp.2017.07.030]
  40. Li H, 2009, BIOINFORMATICS, V25, P2078, DOI 10.1093/bioinformatics/btp352
  41. Li H, 2009, BIOINFORMATICS, V25, P1094, DOI [10.1093/bioinformatics/btp100, 10.1093/bioinformatics/btp324]
  42. Los B, 2023, GENE, V851, DOI 10.1016/j.gene.2022.146979
  43. Los B, 2021, EPIGENOMICS-UK, V13, P779, DOI 10.2217/epi-2020-0462
  44. Maglio C, 2014, J INTERN MED, V276, P396, DOI 10.1111/joim.12263
  45. Mariano C, 2020, CLIN GENET, V97, P457, DOI 10.1111/cge.13697
  46. Marmontel O, 2018, CLIN GENET, V94, P132, DOI 10.1111/cge.13250
  47. Martin M., 2011, EMBNET J, V17, DOI [10.14806/ej.17.1.200, 10.14806/ej.14817.14801.14200, DOI 10.14806/EJ.17.1.200]
  48. McKenna A, 2010, GENOME RES, V20, P1297, DOI 10.1101/gr.107524.110
  49. Molfetta GA, 2017, GENET MOL RES, V16, DOI 10.4238/gmr16039226
  50. Najam O, 2015, CARDIOL THER, V4, P25, DOI 10.1007/s40119-015-0037-z
  51. Neal WA, 2014, CLIN LIPIDOL, V9, P291, DOI 10.2217/CLP.14.19
  52. Nikkola E, 2017, ATHEROSCLEROSIS, V264, P58, DOI 10.1016/j.atherosclerosis.2017.07.024
  53. Noguchi T, 2010, ATHEROSCLEROSIS, V210, P166, DOI 10.1016/j.atherosclerosis.2009.11.018
  54. Nordestgaard BG, 2017, EUR HEART J, V38, P1580, DOI 10.1093/eurheartj/ehx136
  55. Nordestgaard BG, 2013, EUR HEART J, V34, P3478, DOI 10.1093/eurheartj/eht273
  56. Norsworthy PJ, 2014, BMC MED GENET, V15, DOI 10.1186/1471-2350-15-70
  57. Izar MCO, 2022, ARQ BRAS CARDIOL, V118, P678, DOI 10.36660/abc.20220027
  58. Quinlan AR, 2010, BIOINFORMATICS, V26, P841, DOI 10.1093/bioinformatics/btq033
  59. Rader DJ, 2014, CIRCULATION, V129, P1022, DOI 10.1161/CIRCULATIONAHA.113.001292
  60. Richards S, 2015, GENET MED, V17, P405, DOI 10.1038/gim.2015.30
  61. Saadatagah S, 2021, NPJ GENOM MED, V6, DOI 10.1038/s41525-021-00190-z
  62. Salazar LA, 2002, CLIN CHEM LAB MED, V40, P441, DOI 10.1515/CCLM.2002.075
  63. Santos RD, 2017, J CLIN LIPIDOL, V11, P160, DOI 10.1016/j.jacl.2016.11.004
  64. Santos RD, 2016, LANCET DIABETES ENDO, V4, P850, DOI 10.1016/S2213-8587(16)30041-9
  65. Schmidt EB, 2020, HEART, V106, P1940, DOI 10.1136/heartjnl-2019-316276
  66. Sharifi M, 2016, METABOLISM, V65, P48, DOI 10.1016/j.metabol.2015.10.018
  67. Stein EA, 2013, LANCET, V381, P1255, DOI 10.1016/S0140-6736(13)60187-7
  68. Stirling C, 2010, BMC HEALTH SERV RES, V10, DOI 10.1186/1472-6963-10-122
  69. Sturm AC, 2018, J AM COLL CARDIOL, V72, P662, DOI 10.1016/j.jacc.2018.05.044
  70. Talmud PJ, 2013, LANCET, V381, P1293, DOI 10.1016/S0140-6736(12)62127-8
  71. Usifo E, 2012, ANN HUM GENET, V76, P387, DOI 10.1111/j.1469-1809.2012.00724.x
  72. Stormo Gary D, 2013, Curr Protoc Bioinformatics, V43, DOI [10.1002/0471250953.bi1110s43, 10.1002/0471250953.bi1201s43]
  73. Vandrovcova J, 2013, GENET MED, V15, P948, DOI 10.1038/gim.2013.55
  74. Virani SS, 2020, CIRCULATION, V141, pE139, DOI 10.1161/CIR.0000000000000757
  75. Wang J, 2016, ARTERIOSCL THROM VAS, V36, P2439, DOI 10.1161/ATVBAHA.116.308027
  76. Wang K, 2010, NUCLEIC ACIDS RES, V38, DOI 10.1093/nar/gkq603
  77. Wang Y, 2019, BMC PUBLIC HEALTH, V19, DOI 10.1186/s12889-019-7212-4
  78. WHO Human Genetics Programme, 1998, FAM HYP FH REP 2 WHO
  79. Wierzbicki AS, 2008, BMJ-BRIT MED J, V337, DOI 10.1136/bmj.a1095

Coleções
Artigos e Materiais de Revistas Científicas - HC/InCor
Artigos e Materiais de Revistas Científicas - LIM/13
Artigos e Materiais de Revistas Científicas - ODS/03