Abstract
Spinal muscular atrophy is a severe neuromuscular disorder with an autosomal recessive inheritance pattern. The disease-causing gene is SMN1, and its paralogue, SMN2, is a disease course modifier. Both genes SMN1 and SMN2 show over 99.9% sequence identity and a high rate of crossing over in the genomic region. Due to this reason, SMN1/SMN2 is usually excluded from the whole-genome sequencing (WGS) analysis and investigated with traditional methods, such as MLPA and qPCR. Recently, novel bioinformatic algorithms dedicated to analyzing this particular genomic region have been developed. Here, we analyze the SMN1/SMN2 genomic region with a dedicated program, SMNCopyNumberCaller. We report a similar prevalence of SMN1 gene deletion carrier status (1 per 41 people) to published data from the Polish population (1 per 35 people). Additionally, SMNCopyNumberCaller can identify SMN2 CNVs and SMN2Δ7-8 present in 153 healthy Polish individuals. Two other programs for the CNV analysis in standard genomic regions were not able to provide reliable results. Using WGS-based tools for SMN1/2 genomic region analysis is not only an efficient method in terms of time but will also enable more complex analysis such screening for markers related with a silent carrier status and identification of further genetic modifiers. Although still an experimental method, soon WGS-based SMN1/SMN2 carrier identification may become a standard method for patients screened with WGS for other purposes.
References
Ben-Shachar S, Orr-Urtreger A, Bardugo E, Shomrat R, Yaron Y (2011) Large-scale population screening for spinal muscular atrophy: clinical implications. Genet Med 13(2):110–114. https://doi.org/10.1097/GIM.0b013e3182017c05
Burki T (2022) UK explores whole-genome sequencing for newborn babies. Lancet 400(10348):260–261. https://doi.org/10.1016/S0140-6736(22)01378-2
Chan SH, Bylstra Y, Teo JX, Kuan JL, Bertin N, Gonzalez-Porta M, Hebrard M, Tirado-Magallanes R, Tan JHJ, Jeyakani J, Li Z, Chai JF, Chong YS, Davila S, Goh LL, Lee ES, Wong E, Wong TY, SG10K_Health Consortium, Prabhakar S, Liu J, Cheng CY, Eisenhaber B, Karnani N, Leong KP, Sim X, Yeo KK, Chambers JC, Tai ES, Tan P, Jamuar SS, Ngeow J, Lim WK (2022) Analysis of clinically relevant variants from ancestrally diverse Asian genomes. Nat Commun 13(1):6694. https://doi.org/10.1038/s41467-022-34116-9
Chen X, Sanchis-Juan A, French CE, Connell AJ, Delon I, Kingsbury Z, Chawla A, Halpern AL, Taft RJ, NIHR BioResource, Bentley DR, Butchbach MER, Raymond FL, Eberle MA (2020) Spinal muscular atrophy diagnosis and carrier screening from genome sequencing data. Genet Med. 22(5):945–953. https://doi.org/10.1038/s41436-020-0754-0
Feng Y, Ge X, Meng L, Scull J, Li J, Tian X, Zhang T, ** W, Cheng H, Wang X, Tokita M, Liu P, Mei H, Wang Y, Li F, Schmitt ES, Zhang WV, Muzny D, Wen S, Chen Z, Yang Y, Beaudet AL, Liu X, Eng CM, **a F, Wong LJ, Zhang J (2017) The next generation of population-based spinal muscular atrophy carrier screening: comprehensive pan-ethnic SMN1 copy-number and sequence variant analysis by massively parallel sequencing. Genet Med 19(8):936–944. https://doi.org/10.1038/gim.2016.215
Gailite L, Sterna O, Konika M, Isakovs A, Isakova J, Micule I, Setlere S, Diriks M, Auzenbaha M (2022) New-born screening for spinal muscular atrophy: results of a Latvian pilot study. Int J Neonatal Screen 8(1):15. https://doi.org/10.3390/ijns8010015
Gos M, Jędrzejowska M (2022) Strona Polskiego Towarzystwa Genetyki Człowieka Informacja dotycząca badań genetycznych w kierunku SMA. (accessed 23.08.2022) informacja-i-stanowisko-PTGC-PTND_14.03.2022_ost11.pdf
Gregg AR, Aarabi M, Klugman S, Leach NT, Bashford MT, Goldwaser T, Chen E, Sparks TN, Reddi HV, Rajkovic A, Dungan JS, ACMG Professional Practice and Guidelines Committee (2021) Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med 23(10):1793–1806. https://doi.org/10.1038/s41436-021-01203-z
Jedrzejowska M, Milewski M, Zimowski J, Zagozdzon P, Kostera-Pruszczyk A, Borkowska J, Sielska D, Jurek M, Hausmanowa-Petrusewicz I (2010) Incidence of spinal muscular atrophy in Poland–more frequent than predicted? Neuroepidemiology 34(3):152–157. https://doi.org/10.1159/000275492
Kaja E, Lejman A, Sielski D, Sypniewski M, Gambin T, Dawidziuk M, Suchocki T, Golik P, Wojtaszewska M, Mroczek M, Stępień M, Szyda J, Lisiak-Teodorczyk K, Wolbach F, Kołodziejska D, Ferdyn K, Dąbrowski M, Woźna A, Żytkiewicz M, Bodora-Troińska A, Elikowski W, Król ZJ, Zaczyński A, Pawlak A, Gil R, Wierzba W, Dobosz P, Zawadzka K, Zawadzki P, Sztromwasser P (2022) The Thousand Polish Genomes-a database of Polish variant allele frequencies. Int J Mol Sci 23(9):4532. https://doi.org/10.3390/ijms23094532
Larson JL, Silver AJ, Chan D, Borroto C, Spurrier B, Silver LM (2015) Validation of a high resolution NGS method for detecting spinal muscular atrophy carriers among phase 3 participants in the 1000 Genomes Project. BMC Med Genet 16:100. https://doi.org/10.1186/s12881-015-0246-2
Luo M, Liu L, Peter I, Zhu J, Scott SA, Zhao G, Eversley C, Kornreich R, Desnick RJ, Edelmann L (2014) An Ashkenazi Jewish SMN1 haplotype specific to duplication alleles improves pan-ethnic carrier screening for spinal muscular atrophy. Genet Med 16(2):149–156. https://doi.org/10.1038/gim.2013.84
Mandelker D, Schmidt RJ, Ankala A, McDonald Gibson K, Bowser M, Sharma H, Duffy E, Hegde M, Santani A, Lebo M, Funke B (2016) Navigating highly homologous genes in a molecular diagnostic setting: a resource for clinical next-generation sequencing. Genet Med 18(12):1282–1289. https://doi.org/10.1038/gim.2016.58
Prior T, for the Professional Practice and Guidelines Committee (2008) Carrier screening for spinal muscular atrophy. Genet Med 10:840–842. https://doi.org/10.1097/GIM.0b013e318188d069
Prior TW, Leach ME, Finanger E (2000) Spinal muscular atrophy. [Updated 2020 Dec 3]. In: Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1. Accessed 08 Jan 2022
Romanelli Tavares VL, Monfardini F, Lourenço NCV, da Rocha KM, Weinmann K, Pavanello R, Zatz M (2021) Newborn screening for 5q spinal muscular atrophy: comparisons between real-time PCR methodologies and cost estimations for future implementation programs. Int J Neonatal Screen 7(3):53. https://doi.org/10.3390/ijns7030053
Sugarman EA, Nagan N, Zhu H, Akmaev VR, Zhou Z, Rohlfs EM, Flynn K, Hendrickson BC, Scholl T, Sirko-Osadsa DA, Allitto BA (2012) Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens. Eur J Hum Genet 20(1):27–32. https://doi.org/10.1038/ejhg.2011.134
Vijzelaar R, Snetselaar R, Clausen M, Mason AG, Rinsma M, Zegers M, Molleman N, Boschloo R, Yilmaz R, Kuilboer R, Lens S, Sulchan S, Schouten J (2019) The frequency of SMN gene variants lacking exon 7 and 8 is highly population dependent. PLoS ONE 14(7):e0220211. https://doi.org/10.1371/journal.pone.0220211
Zhao S, Wang W, Wang Y, Han R, Fan C, Ni P, Guo F, Zeng F, Yang Q, Yang Y, Sun Y, Zhang X, Chen Y, Zhu B, Cai W, Chen S, Cai R, Guo X, Zhang C, Zhou Y, Huang S, Liu Y, Chen B, Yan S, Chen Y, Ding H, Shang X, Xu X, Sun J, Peng Z (2021) NGS-based spinal muscular atrophy carrier screening of 10,585 diverse couples in China: a pan-ethnic study. Eur J Hum Genet 29(1):194–204. https://doi.org/10.1038/s41431-020-00714-8
Funding
This work was supported by the National Centre for Research and Development Grant No. SZPITALE-JEDNOIMIENNE/2/2020 and by the Medical Research Agency Grant No. 2020/ABM/ COVID19/0022.
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Conceptualization—MM. Formal analysis—DK, PD, and MS. Funding acquisition, investigation, and methodology—PS, DK, MS, and MM. Supervision—MM, PD, and PS. Writing original draft—MM, DK, and MS. Writing review and editing—LK and PD. All authors have read and agreed to the published version of the manuscript.
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The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Ethics Committee of the Central Clinical Hospital of the Ministry of Interior and Administration in Warsaw (decision nr: 41/2020 from 03.04.2020 and 125/2020 from 1.07.2020).
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Sypniewski, M., Kresa, D., Dobosz, P. et al. Population WGS-based spinal muscular atrophy carrier screening in a cohort of 1076 healthy Polish individuals. J Appl Genetics 64, 135–139 (2023). https://doi.org/10.1007/s13353-022-00737-5
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DOI: https://doi.org/10.1007/s13353-022-00737-5