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Missense mutation
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== Screening == === Next Generation Sequencing (NGS) === Next Generation Sequencing (NGS) has changed the world of sequencing by decreasing the cost of sequencing and increasing the throughput.<ref>{{Cite journal |last=Chang |first=Fengqi |last2=Li |first2=Marilyn M. |date=2013-12-01 |title=Clinical application of amplicon-based next-generation sequencing in cancer |url=https://linkinghub.elsevier.com/retrieve/pii/S2210776213001427 |journal=Cancer Genetics |series=Next Generation Sequencing in Clinical Cancer Genomics |volume=206 |issue=12 |pages=413β419 |doi=10.1016/j.cancergen.2013.10.003 |issn=2210-7762|url-access=subscription }}</ref> It does this by utilizing [[Massive parallel sequencing|massively parallel sequencing]] to sequence the genome. This involves clonally amplified [[DNA]] fragments that can be spatially separated into second generation sequencing (SGS) or third generation sequencing (TGS) platforms.<ref>{{Cite book | vauthors = Xu J |title=Next-generation sequencing: current technologies and applicaitons |date=2014 |publisher=Caister academic press |isbn=978-1-908230-33-1 |location=Norfolk}}</ref> There is variation between these protocols, but the overall methods are similar. Using massively parallel sequencing allows the NGS platform to produce very large sequences in a single run.<ref name="Valencia_2013">{{Cite book | vauthors = Valencia CA, Pervaiz MA, Husami A, Qian Y, Zhang K | title = Next Generation Sequencing Technologies in Medical Genetics |date=2013 |publisher=Springer New York |isbn=978-1-4614-9031-9 |series=SpringerBriefs in Genetics |location=New York, NY |language=en |doi=10.1007/978-1-4614-9032-6}}</ref> The DNA fragments are typically separated by length using gel electrophoresis. NGS consists of four main steps, DNA isolation, target enrichment, sequencing, and data analysis.<ref name="Valencia_2013" /> The DNA isolation step involves breaking the genomic DNA into many small fragments.<ref name="Qin_2019" /> There are many different mechanisms that can be used to accomplish this such as mechanical methods, enzymatic digestion, and more.<ref name="Qin_2019">{{cite journal | vauthors = Qin D | title = Next-generation sequencing and its clinical application | journal = Cancer Biology & Medicine | volume = 16 | issue = 1 | pages = 4β10 | date = February 2019 | pmid = 31119042 | doi = 10.20892/j.issn.2095-3941.2018.0055 | pmc = 6528456 }}</ref> This step also consists of adding adaptors to either end of the DNA fragments that are complementary to the flow cell oligos and include primer binding sites for the target DNA.<ref name="Valencia_2013" /> The target enrichment step amplifies the region of interest. This includes creating a complementary strand to the DNA fragments through hybridization to a flow cell oligo.<ref name="Valencia_2013" /> It then gets denatured and bridge amplification occurs before the reverse strand is finally washed and sequencing can occur. The sequencing step involves massive parallel sequencing of all DNA fragments simultaneously using a NGS sequencer. This information is saved and analyzed in the last step, data analysis, using bioinformatics software.<ref name="Qin_2019" /> This compares the sequences to a reference genome to align the fragments and show mutations in the targeted area of the sequence.<ref name="Qin_2019" /> === Newborn Screening (NBS) === [[Newborn screening]] (NBS) for missense mutations is increasingly incorporating genomic technologies in addition to traditional biochemical methods to improve the detection of genetic disorders early in life. Traditional NBS primarily relies on biochemical assays, such as [[tandem mass spectrometry]],<ref>{{Cite journal |last=Levy |first=Harvey L |date=1998-12-01 |title=Newborn Screening by Tandem Mass Spectrometry: A New Era |url=https://academic.oup.com/clinchem/article/44/12/2401/5643158 |journal=Clinical Chemistry |language=en |volume=44 |issue=12 |pages=2401β2402 |doi=10.1093/clinchem/44.12.2401 |pmid=9836702 |issn=0009-9147}}</ref> to detect metabolic abnormalities indicative of conditions like [[phenylketonuria]] or [[congenital hypothyroidism]].<ref>{{Cite journal |last=Cunningham |first=George |date=2002-04-04 |title=The Science and Politics of Screening Newborns |url=http://www.nejm.org/doi/abs/10.1056/NEJM200204043461411 |journal=New England Journal of Medicine |language=en |volume=346 |issue=14 |pages=1084β1085 |doi=10.1056/NEJM200204043461411 |pmid=11932477 |issn=0028-4793|url-access=subscription }}</ref> However, these methods may miss genetic causes or produce ambiguous results. To address these deficiencies, [[next-generation sequencing]] (NGS) is being added to NBS programs.<ref>{{Cite journal |last1=Remec |first1=Ziga I. |last2=Trebusak Podkrajsek |first2=Katarina |last3=Repic Lampret |first3=Barbka |last4=Kovac |first4=Jernej |last5=Groselj |first5=Urh |last6=Tesovnik |first6=Tine |last7=Battelino |first7=Tadej |last8=Debeljak |first8=Marusa |date=2021-05-26 |title=Next-Generation Sequencing in Newborn Screening: A Review of Current State |journal=Frontiers in Genetics |volume=12 |doi=10.3389/fgene.2021.662254 |doi-access=free |issn=1664-8021 |pmc=8188483 |pmid=34122514}}</ref> For instance, targeted gene panels and [[whole-exome sequencing]] (WES) are used to identify disease causing missense mutations in genes associated with treatable conditions, such as [[severe combined immunodeficiency]] (SCID) and [[cystic fibrosis]]. Studies like the BabyDetect project have demonstrated the utility of genomic screening in identifying disorders missed by conventional methods, with actionable results for conditions affecting more than 400 genes.<ref name="Boemer_2025">{{cite journal | vauthors = Boemer F, Hovhannesyan K, Piazzon F, Minner F, Mni M, Jacquemin V, Mashhadizadeh D, Benmhammed N, Bours V, Jacquinet A, Harvengt J, Bulk S, Dideberg V, Helou L, Palmeira L, Dangouloff T, Servais L | title = Population-based, first-tier genomic newborn screening in the maternity ward | journal = Nature Medicine | volume = | issue = | pages = | date = January 2025 | pmid = 39875687 | doi = 10.1038/s41591-024-03465-x | doi-access = free | pmc = 12003153 }}</ref><ref>{{cite book | vauthors = Rai P, Mamcarz EK, Hankins JS | chapter = Newborn Genetic Screening for Blood Disorders | veditors = de AlarcΓ³n PA, Werner EJ, Christensen RD | title = Neonatal Hematology: Pathogenesis, Diagnosis, and Management of Hematologic Problems | edition = 3rd | date = 2021 | publisher = Cambridge University Press | location = Cambridge |isbn=978-1-108-48898-3 }}</ref> In addition, genomic approaches allow for the detection of rare or recessive conditions that may not manifest biochemically at birth, significantly expanding the scope of diseases screened.<ref name="pmid37656463">{{cite journal | vauthors = Jiang S, Wang H, Gu Y | title = Genome Sequencing for Newborn Screening-An Effective Approach for Tackling Rare Diseases | journal = JAMA Network Open | volume = 6 | issue = 9 | pages = e2331141 | date = September 2023 | pmid = 37656463 | doi = 10.1001/jamanetworkopen.2023.31141 | url = | doi-access = free }}</ref> These advancements align with the established principles of NBS, which emphasize early detection and intervention to prevent morbidity and mortality.<ref>{{cite book | vauthors = Clarke JT | chapter = Newborn screening. | title = A Clinical Guide to Inherited Metabolic Diseases. | location = Cambridge | publisher = Cambridge University Press | date = 2005 | pages = 228β240 | isbn = 978-0-511-54468-2 | doi = 10.1017/CBO9780511544682.011 }}</ref>
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