Usefulness and Limitations of Multiple Ligation-Dependent Probe Amplification in Antithrombin Deficiency
Multiplex ligation-dependent probe amplification (MLPA) identifies genetic structural variants in in 5% of cases with antithrombin deficiency (ATD), the most severe congenital thrombophilia. Our aim was to unravel the utility and limitations of MLPA in a large cohort of unrelated patients with ATD (...
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| Veröffentlicht in: | International journal of molecular sciences 2023-03, Vol.24 (5), p.5023 |
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| creator | Cifuentes, Rosa Padilla, José de la Morena-Barrio, María Eugenia de la Morena-Barrio, Belén Bravo-Pérez, Carlos Garrido-Rodríguez, Pedro Llamas, María Miñano, Antonia Vicente, Vicente Lozano, María Luisa Corral, Javier |
| description | Multiplex ligation-dependent probe amplification (MLPA) identifies genetic structural variants in
in 5% of cases with antithrombin deficiency (ATD), the most severe congenital thrombophilia. Our aim was to unravel the utility and limitations of MLPA in a large cohort of unrelated patients with ATD (N = 341). MLPA identified 22 structural variants (SVs) causing ATD (6.5%). MLPA did not detect SVs affecting introns (four cases), and the diagnosis was inaccurate in two cases according to long-range PCR or nanopore sequencing. MLPA was used to detect possible hidden SVs in 61 cases with type I deficiency with single nucleotide variations (SNVs) or small insertion/deletion (INDEL). One case had a false deletion of exon 7, as the 29-bp deletion affected an MLPA probe. We evaluated 32 variants affecting MLPA probes: 27 SNVs and 5 small INDELs. In three cases, MLPA gave false-positive results, all diagnosed as deletions of the affected exon: a small INDEL complex, and two SNVs affecting MLPA probes. Our study confirms the utility of MLPA to detect SVs in ATD, but also shows some limitations in detecting intronic SVs. MLPA renders imprecise and false-positive results for genetic defects which affect MLPA probes. Our results encourage the validation of MLPA results. |
| doi_str_mv | 10.3390/ijms24055023 |
| format | Article |
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in 5% of cases with antithrombin deficiency (ATD), the most severe congenital thrombophilia. Our aim was to unravel the utility and limitations of MLPA in a large cohort of unrelated patients with ATD (N = 341). MLPA identified 22 structural variants (SVs) causing ATD (6.5%). MLPA did not detect SVs affecting introns (four cases), and the diagnosis was inaccurate in two cases according to long-range PCR or nanopore sequencing. MLPA was used to detect possible hidden SVs in 61 cases with type I deficiency with single nucleotide variations (SNVs) or small insertion/deletion (INDEL). One case had a false deletion of exon 7, as the 29-bp deletion affected an MLPA probe. We evaluated 32 variants affecting MLPA probes: 27 SNVs and 5 small INDELs. In three cases, MLPA gave false-positive results, all diagnosed as deletions of the affected exon: a small INDEL complex, and two SNVs affecting MLPA probes. Our study confirms the utility of MLPA to detect SVs in ATD, but also shows some limitations in detecting intronic SVs. MLPA renders imprecise and false-positive results for genetic defects which affect MLPA probes. Our results encourage the validation of MLPA results.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms24055023</identifier><identifier>PMID: 36902454</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Algorithms ; Anticoagulants ; Antigens ; Antithrombin ; Antithrombins ; Defects ; DNA sequencing ; Exons ; Gene deletion ; Genetic disorders ; Genetic engineering ; Genomes ; Humans ; Introns ; Investigations ; Methods ; Multiplex Polymerase Chain Reaction - methods ; Mutation ; Nucleotide sequencing ; Nucleotides ; Patients ; Plasma ; Probes ; Thrombophilia ; Thrombophilia - genetics ; Thrombosis</subject><ispartof>International journal of molecular sciences, 2023-03, Vol.24 (5), p.5023</ispartof><rights>COPYRIGHT 2023 MDPI AG</rights><rights>2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2023 by the authors. 2023</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c480t-7059189378eaf9ced9c7bb3a0ff75927081e79c5f996171a0705b5851e0d51b3</citedby><cites>FETCH-LOGICAL-c480t-7059189378eaf9ced9c7bb3a0ff75927081e79c5f996171a0705b5851e0d51b3</cites><orcidid>0000-0003-3447-248X ; 0000-0001-7426-4947 ; 0000-0002-4278-3264 ; 0000-0003-3148-7037 ; 0000-0001-9794-7847</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10002544/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10002544/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27903,27904,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36902454$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cifuentes, Rosa</creatorcontrib><creatorcontrib>Padilla, José</creatorcontrib><creatorcontrib>de la Morena-Barrio, María Eugenia</creatorcontrib><creatorcontrib>de la Morena-Barrio, Belén</creatorcontrib><creatorcontrib>Bravo-Pérez, Carlos</creatorcontrib><creatorcontrib>Garrido-Rodríguez, Pedro</creatorcontrib><creatorcontrib>Llamas, María</creatorcontrib><creatorcontrib>Miñano, Antonia</creatorcontrib><creatorcontrib>Vicente, Vicente</creatorcontrib><creatorcontrib>Lozano, María Luisa</creatorcontrib><creatorcontrib>Corral, Javier</creatorcontrib><title>Usefulness and Limitations of Multiple Ligation-Dependent Probe Amplification in Antithrombin Deficiency</title><title>International journal of molecular sciences</title><addtitle>Int J Mol Sci</addtitle><description>Multiplex ligation-dependent probe amplification (MLPA) identifies genetic structural variants in
in 5% of cases with antithrombin deficiency (ATD), the most severe congenital thrombophilia. Our aim was to unravel the utility and limitations of MLPA in a large cohort of unrelated patients with ATD (N = 341). MLPA identified 22 structural variants (SVs) causing ATD (6.5%). MLPA did not detect SVs affecting introns (four cases), and the diagnosis was inaccurate in two cases according to long-range PCR or nanopore sequencing. MLPA was used to detect possible hidden SVs in 61 cases with type I deficiency with single nucleotide variations (SNVs) or small insertion/deletion (INDEL). One case had a false deletion of exon 7, as the 29-bp deletion affected an MLPA probe. We evaluated 32 variants affecting MLPA probes: 27 SNVs and 5 small INDELs. In three cases, MLPA gave false-positive results, all diagnosed as deletions of the affected exon: a small INDEL complex, and two SNVs affecting MLPA probes. Our study confirms the utility of MLPA to detect SVs in ATD, but also shows some limitations in detecting intronic SVs. MLPA renders imprecise and false-positive results for genetic defects which affect MLPA probes. Our results encourage the validation of MLPA results.</description><subject>Algorithms</subject><subject>Anticoagulants</subject><subject>Antigens</subject><subject>Antithrombin</subject><subject>Antithrombins</subject><subject>Defects</subject><subject>DNA sequencing</subject><subject>Exons</subject><subject>Gene deletion</subject><subject>Genetic disorders</subject><subject>Genetic engineering</subject><subject>Genomes</subject><subject>Humans</subject><subject>Introns</subject><subject>Investigations</subject><subject>Methods</subject><subject>Multiplex Polymerase Chain Reaction - methods</subject><subject>Mutation</subject><subject>Nucleotide sequencing</subject><subject>Nucleotides</subject><subject>Patients</subject><subject>Plasma</subject><subject>Probes</subject><subject>Thrombophilia</subject><subject>Thrombophilia - genetics</subject><subject>Thrombosis</subject><issn>1422-0067</issn><issn>1661-6596</issn><issn>1422-0067</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNptks9PHCEUx4mpqVZ789xM0ksPHQVmGIaT2aj9kaxpD3omDPPYZcPAFGaa-N_LqrWrMRyA9z7vC--bh9AJwadVJfCZ3QyJ1pgxTKs9dEhqSkuMG_5u53yAPqS0wZmgTLxHB1UjMK1ZfYjWtwnM7DykVCjfF0s72ElNNvhUBFNcz26yo4McXz1Ey0sYwffgp-J3DB0Ui2F01lj9kC2sLxZ-stM6hqHLl0vIKQte3x2jfaNcgo9P-xG6-XZ1c_GjXP76_vNisSx13eKp5JgJ0oqKt6CM0NALzbuuUtgYzgTluCXAhWZGiIZwonAu6FjLCOCeka46QuePsuPcDdDr_NGonByjHVS8k0FZ-TLj7Vquwl9JcLaH1XVW-PKkEMOfGdIkB5s0OKc8hDlJytsGi2z3Fv38Ct2EOfrc3pZilFLWtP-plXIgrTchP6y3onLBGRG0yVymTt-g8uphsDr4bGSOvyj4-ligY0gpgnlukmC5nQy5OxkZ_7RrzDP8bxSqezQPs9g</recordid><startdate>20230301</startdate><enddate>20230301</enddate><creator>Cifuentes, Rosa</creator><creator>Padilla, José</creator><creator>de la Morena-Barrio, María Eugenia</creator><creator>de la Morena-Barrio, Belén</creator><creator>Bravo-Pérez, Carlos</creator><creator>Garrido-Rodríguez, Pedro</creator><creator>Llamas, María</creator><creator>Miñano, Antonia</creator><creator>Vicente, Vicente</creator><creator>Lozano, María Luisa</creator><creator>Corral, Javier</creator><general>MDPI AG</general><general>MDPI</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-3447-248X</orcidid><orcidid>https://orcid.org/0000-0001-7426-4947</orcidid><orcidid>https://orcid.org/0000-0002-4278-3264</orcidid><orcidid>https://orcid.org/0000-0003-3148-7037</orcidid><orcidid>https://orcid.org/0000-0001-9794-7847</orcidid></search><sort><creationdate>20230301</creationdate><title>Usefulness and Limitations of Multiple Ligation-Dependent Probe Amplification in Antithrombin Deficiency</title><author>Cifuentes, Rosa ; 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in 5% of cases with antithrombin deficiency (ATD), the most severe congenital thrombophilia. Our aim was to unravel the utility and limitations of MLPA in a large cohort of unrelated patients with ATD (N = 341). MLPA identified 22 structural variants (SVs) causing ATD (6.5%). MLPA did not detect SVs affecting introns (four cases), and the diagnosis was inaccurate in two cases according to long-range PCR or nanopore sequencing. MLPA was used to detect possible hidden SVs in 61 cases with type I deficiency with single nucleotide variations (SNVs) or small insertion/deletion (INDEL). One case had a false deletion of exon 7, as the 29-bp deletion affected an MLPA probe. We evaluated 32 variants affecting MLPA probes: 27 SNVs and 5 small INDELs. In three cases, MLPA gave false-positive results, all diagnosed as deletions of the affected exon: a small INDEL complex, and two SNVs affecting MLPA probes. Our study confirms the utility of MLPA to detect SVs in ATD, but also shows some limitations in detecting intronic SVs. MLPA renders imprecise and false-positive results for genetic defects which affect MLPA probes. Our results encourage the validation of MLPA results.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>36902454</pmid><doi>10.3390/ijms24055023</doi><orcidid>https://orcid.org/0000-0003-3447-248X</orcidid><orcidid>https://orcid.org/0000-0001-7426-4947</orcidid><orcidid>https://orcid.org/0000-0002-4278-3264</orcidid><orcidid>https://orcid.org/0000-0003-3148-7037</orcidid><orcidid>https://orcid.org/0000-0001-9794-7847</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Algorithms Anticoagulants Antigens Antithrombin Antithrombins Defects DNA sequencing Exons Gene deletion Genetic disorders Genetic engineering Genomes Humans Introns Investigations Methods Multiplex Polymerase Chain Reaction - methods Mutation Nucleotide sequencing Nucleotides Patients Plasma Probes Thrombophilia Thrombophilia - genetics Thrombosis |
| title | Usefulness and Limitations of Multiple Ligation-Dependent Probe Amplification in Antithrombin Deficiency |
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