Journal of Genetic Medicine

Korean Society of Medical Genetics and Genomics (대한의학유전학회)
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Exonic copy number variations in rare genetic disorders

  • Man Jin Kim (Department of Genomic Medicine, Seoul National University Hospital)
  • Received : 2023.11.23
  • Accepted : 2023.12.04
  • Published : 2023.12.31
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Abstract

Exonic copy number variation (CNV), involving deletions and duplications at the gene's exon level, presents challenges in detection due to their variable impact on gene function. The study delves into the complexities of identifying large CNVs and investigates less familiar but recurrent exonic CNVs, notably enriched in East Asian populations. Examining specific cases like DRC1, STX16, LAMA2, and CFTR highlights the clinical implications and prevalence of exonic CNVs in diverse populations. The review addresses diagnostic challenges, particularly for single exon alterations, advocating for a strategic, multi-method approach. Diagnostic methods, including multiplex ligation-dependent probe amplification, droplet digital PCR, and CNV screening using next-generation sequencing data, are discussed, with whole genome sequencing emerging as a powerful tool. The study underscores the crucial role of ethnic considerations in understanding specific CNV prevalence and ongoing efforts to unravel subtle variations. The ultimate goal is to advance rare disease diagnosis and treatment through ethnically-specific therapeutic interventions.

Keywords

References

  1. Henrichsen CN, Chaignat E, Reymond A. Copy number variants, diseases and gene expression. Hum Mol Genet 2009;18:R1-8. https://doi.org/10.1093/hmg/ddp011
  2. Rigau M, Juan D, Valencia A, Rico D. Intronic CNVs and gene expression variation in human populations. PLoS Genet 2019;15:e1007902.
  3. Lee C, Scherer SW. The clinical context of copy number variation in the human genome. Expert Rev Mol Med 2010;12:e8.
  4. Kozareva V, Stroff C, Silver M, Freidin JF, Delaney NF. Clinical analysis of germline copy number variation in DMD using a non-conjugate hierarchical Bayesian model. BMC Med Genomics 2018;11:91.
  5. Wei X, Dai Y, Yu P, Qu N, Lan Z, Hong X, et al. Targeted next-generation sequencing as a comprehensive test for patients with and female carriers of DMD/BMD: a multi-population diagnostic study. Eur J Hum Genet 2014;22:110-8. https://doi.org/10.1038/ejhg.2013.82
  6. Passon N, Dubsky de Wittenau G, Jurman I, Radovic S, Bregant E, Molinis C, et al. Quick MLPA test for quantification of SMN1 and SMN2 copy numbers. Mol Cell Probes 2010;24:310-4. https://doi.org/10.1016/j.mcp.2010.07.001
  7. Vijzelaar R, Snetselaar R, Clausen M, Mason AG, Rinsma M, Zegers M, et al. The frequency of SMN gene variants lacking exon 7 and 8 is highly population dependent. PLoS One 2019;14:e0220211.
  8. Keicho N, Hijikata M, Morimoto K, Homma S, Taguchi Y, Azuma A, et al. Primary ciliary dyskinesia caused by a large homozygous deletion including exons 1-4 of DRC1 in Japanese patients with recurrent sinopulmonary infection. Mol Genet Genomic Med 2020;8:e1033.
  9. Kim MJ, Kim S, Chae SW, Lee S, Yoon JG, Kim B, et al. Prevalence and founder effect of DRC1 exon 1-4 deletion in Korean patients with primary ciliary dyskinesia. J Hum Genet 2023;68:369-74. https://doi.org/10.1038/s10038-023-01122-8
  10. Morimoto K, Hijikata M, Zariwala MA, Nykamp K, Inaba A, Guo TC, et al. Recurring large deletion in DRC1 (CCDC164) identified as causing primary ciliary dyskinesia in two Asian patients. Mol Genet Genomic Med 2019;7:e838.
  11. Chu X, Zhu Y, Wang O, Nie M, Quan T, Xue Y, et al. Clinical and genetic characteristics of Pseudohypoparathyroidism in the Chinese population. Clin Endocrinol (Oxf) 2018;88:285-94. https://doi.org/10.1111/cen.13516
  12. Danzig J, Li D, Jan de Beur S, Levine MA. High-throughput molecular analysis of pseudohypoparathyroidism 1b patients reveals novel genetic and epigenetic defects. J Clin Endocrinol Metab 2021;106:e4603-20. https://doi.org/10.1210/clinem/dgab460
  13. Elli FM, de Sanctis L, Peverelli E, Bordogna P, Pivetta B, Miolo G, et al. Autosomal dominant pseudohypoparathyroidism type Ib: a novel inherited deletion ablating STX16 causes loss of imprinting at the A/B DMR. J Clin Endocrinol Metab 2014;99:E724-8. https://doi.org/10.1210/jc.2013-3704
  14. Juppner H. Molecular definition of pseudohypoparathyroidism variants. J Clin Endocrinol Metab 2021;106:1541-52. https://doi.org/10.1210/clinem/dgab060
  15. Kiuchi Z, Reyes M, Brickman AS, Juppner H. A distinct variant of pseudohypoparathyroidism (PHP) first characterized some 41years ago is caused by the 3-kbSTX16 deletion. JBMR Plus 2021;5:e10505.
  16. Linglart A, Gensure RC, Olney RC, Juppner H, Bastepe M. A novel STX16 deletion in autosomal dominant pseudohypoparathyroidism type Ib redefines the boundaries of a cis-acting imprinting control element of GNAS. Am J Hum Genet 2005;76:804-14. Erratum in: Am J Hum Genet 2007;81:196.
  17. Ramalho E Silva JD, da Rocha GFMA, Oliveira MJM. An intricate case of sporadic pseudohypoparathyroidism type 1B with a review of literature. Arch Endocrinol Metab 2021;65:112-6.
  18. Ge L, Liu A, Gao K, Du R, Ding J, Mao B, et al. Deletion of exon 4 in LAMA2 is the most frequent mutation in Chinese patients with laminin α2-related muscular dystrophy. Sci Rep 2018;8:14989.
  19. Palomaki GE, FitzSimmons SC, Haddow JE. Clinical sensitivity of prenatal screening for cystic fibrosis via CFTR carrier testing in a United States panethnic population. Genet Med 2004;6:405-14. https://doi.org/10.1097/01.GIM.0000139505.06194.39
  20. Sohn YB, Ko JM, Jang JY, Seong MW, Park SS, Suh DI, et al. Deletion of exons 16-17b of CFTR is frequently identified in Korean patients with cystic fibrosis. Eur J Med Genet 2019;62:103681.
  21. Hindson BJ, Ness KD, Masquelier DA, Belgrader P, Heredia NJ, Makarewicz AJ, et al. High-throughput droplet digital PCR system for absolute quantitation of DNA copy number. Anal Chem 2011;83:8604-10. https://doi.org/10.1021/ac202028g
  22. Hindson CM, Chevillet JR, Briggs HA, Gallichotte EN, Ruf IK, Hindson BJ, et al. Absolute quantification by droplet digital PCR versus analog real-time PCR. Nat Methods 2013;10:1003-5. https://doi.org/10.1038/nmeth.2633
  23. Coccaro N, Tota G, Anelli L, Zagaria A, Specchia G, Albano F. Digital PCR: a reliable tool for analyzing and monitoring hematologic malignancies. Int J Mol Sci 2020;21:3141.
  24. Zhou B, Haney MS, Zhu X, Pattni R, Abyzov A, Urban AE. Detection and quantification of mosaic genomic DNA variation in primary somatic tissues using ddPCR: analysis of mosaic transposable-element insertions, copy-number variants, and single-nucleotide variants. Methods Mol Biol 2018;1768:173-90. https://doi.org/10.1007/978-1-4939-7778-9_11
  25. Zhao Y, Xia Q, Yin Y, Wang Z. Comparison of droplet digital PCR and quantitative PCR assays for quantitative detection of Xanthomonas citri Subsp. citri. PLoS One 2016;11:e0159004.
  26. Moreno-Cabrera JM, Del Valle J, Castellanos E, Feliubadalo L, Pineda M, Brunet J, et al. Evaluation of CNV detection tools for NGS panel data in genetic diagnostics. Eur J Hum Genet 2020;28:1645-55. https://doi.org/10.1038/s41431-020-0675-z
  27. Singh AK, Olsen MF, Lavik LAS, Vold T, Drablos F, Sjursen W. Detecting copy number variation in next generation sequencing data from diagnostic gene panels. BMC Med Genomics 2021;14:214.
  28. Zhao M, Wang Q, Wang Q, Jia P, Zhao Z. Computational tools for copy number variation (CNV) detection using next-generation sequencing data: features and perspectives. BMC Bioinformatics 2013;14 Suppl 11:S1.
  29. Chen X, Schulz-Trieglaff O, Shaw R, Barnes B, Schlesinger F, Kallberg M, et al. Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications. Bioinformatics 2016;32:1220-2. https://doi.org/10.1093/bioinformatics/btv710
  30. Rausch T, Zichner T, Schlattl A, Stutz AM, Benes V, Korbel JO. DELLY: structural variant discovery by integrated paired-end and split-read analysis. Bioinformatics 2012;28:i333-9. https://doi.org/10.1093/bioinformatics/bts378
  31. Coutelier M, Holtgrewe M, Jager M, Flottman R, Mensah MA, Spielmann M, et al. Combining callers improves the detection of copy number variants from whole-genome sequencing. Eur J Hum Genet 2022;30:178-86. https://doi.org/10.1038/s41431-021-00983-x
  32. Fan DM, Yang X, Huang LM, Ouyang GJ, Yang XX, Li M. Simultaneous detection of target CNVs and SNVs of thalassemia by multiplex PCR and next-generation sequencing. Mol Med Rep 2019;19:2837-48. https://doi.org/10.3892/mmr.2019.9896
  33. Takeuchi K, Xu Y, Kitano M, Chiyonobu K, Abo M, Ikegami K, et al. Copy number variation in DRC1 is the major cause of primary ciliary dyskinesia in the Japanese population. Mol Genet Genomic Med 2020;8:e1137.