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Long-read genome sequencing resolves a de novo complex 18q12.1q21.2 triplication causing partial tetrasomy and reveals its underlying mechanism.

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Τίτλος: Long-read genome sequencing resolves a de novo complex 18q12.1q21.2 triplication causing partial tetrasomy and reveals its underlying mechanism.
Συγγραφείς: Redaelli S; School of Medicine and Surgery, University of Milano-Bicocca, Monza, 20900, Italy., Tritto V; Department of Medical Biotechnology and Translational Medicine (BIOMETRA), University of Milan, Milan, 20122, Italy., Mangano E; Institute for Biomedical Technologies (ITB), National Research Council (CNR), Segrate, 20054, Italy., Bordoni R; Institute for Biomedical Technologies (ITB), National Research Council (CNR), Segrate, 20054, Italy., Sala E; UC Medical Genetics, Fondazione IRCCS San Gerardo dei Tintori, Monza, 20900, Italy., Villa N; UC Medical Genetics, Fondazione IRCCS San Gerardo dei Tintori, Monza, 20900, Italy., Crosti F; UC Medical Genetics, Fondazione IRCCS San Gerardo dei Tintori, Monza, 20900, Italy., Dalprà L; School of Medicine and Surgery, University of Milano-Bicocca, Monza, 20900, Italy.; UC Medical Genetics, Fondazione IRCCS San Gerardo dei Tintori, Monza, 20900, Italy., Spaccini L; Clinical Genetics Unit, Department of Obstetrics and Gynecology, Vittore Buzzi Children's Hospital, University of Milan, Milan, 20122, Italy., Sirtori A; Scuola di Specializzazione in Genetica Medica, University of Milano-Bicocca, Monza, 20900, Italy., Cazzaniga G; School of Medicine and Surgery, University of Milano-Bicocca, Monza, 20900, Italy.; UC Medical Genetics, Fondazione IRCCS San Gerardo dei Tintori, Monza, 20900, Italy., Conconi D; School of Medicine and Surgery, University of Milano-Bicocca, Monza, 20900, Italy., Bentivegna A; School of Medicine and Surgery, University of Milano-Bicocca, Monza, 20900, Italy. angela.bentivegna@unimib.it.; UC Medical Genetics, Fondazione IRCCS San Gerardo dei Tintori, Monza, 20900, Italy. angela.bentivegna@unimib.it., Riva P; Department of Medical Biotechnology and Translational Medicine (BIOMETRA), University of Milan, Milan, 20122, Italy. paola.riva@unimi.it.
Πηγή: Human genetics [Hum Genet] 2026 Jul 04; Vol. 145 (1). Date of Electronic Publication: 2026 Jul 04.
Τύπος έκδοσης: Journal Article; Case Reports
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Springer Verlag Country of Publication: Germany NLM ID: 7613873 Publication Model: Electronic Cited Medium: Internet ISSN: 1432-1203 (Electronic) Linking ISSN: 03406717 NLM ISO Abbreviation: Hum Genet Subsets: MEDLINE
Imprint Name(s): Publication: Berlin : Springer Verlag
Original Publication: Berlin, New York, Springer-Verlag.
Ιατρικοί όροι (MeSH): Chromosomes, Human, Pair 18*/genetics , Tetrasomy*/genetics , Triploidy*, Humans ; Female ; Loss of Heterozygosity ; Pregnancy ; Karyotyping ; Comparative Genomic Hybridization
Περίληψη: Chromosomal triplications are rare structural variations often associated with complex phenotypes. We report the molecular characterization of a novel intrachromosomal triplication at 18q12.1q21.2 identified in a fetus with ultrasound abnormalities. Conventional karyotyping and array-CGH revealed a partial tetrasomy and a 26 Mb region of loss of homozygosity (LOH), extending from the triplication to the telomere. Long-read sequencing (LRS) identified breakpoint junctions revealing a direct-inverted-direct triplication structure. Breakpoint analysis suggested that this rearrangement arose through a U-type exchange between sister chromatids, likely mediated by microhomology-based mechanisms. This process likely generated a transient dicentric chromosome that subsequently broke during mitosis. The resulting duplicated chromosome may have been stabilized by telomere capture, consistent with the triplicated 18q12.1q21.2 region followed by the 18q21.2q23 LOH. Nine genes within the triplicated region, including SMAD2 and SMAD4, showed high predicted sensitivity to increased dosage, possibly contributing to the clinical phenotype. This study highlights the utility of LRS in defining complex chromosomal rearrangements and emphasizes the importance of molecular breakpoint analysis for understanding pathogenic mechanisms and improving genetic prenatal diagnosis.
(© 2026. The Author(s).)
Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests. Ethical approval: We followed the guidelines of the ethics committee of the Fondazione IRCCS San Gerardo dei Tintori, Monza. Consent to participate: Informed consent was obtained from parents’ participants included in the study. Consent for publication: Participants signed informed consent regarding publishing the data.
References: Front Cell Dev Biol. 2022 Mar 22;10:825345. (PMID: 35392164)
Am J Med Genet A. 2024 Mar;194(3):e63457. (PMID: 37881147)
Nat Rev Genet. 2016 Apr;17(4):224-38. (PMID: 26924765)
Genome Med. 2025 Jan 20;17(1):6. (PMID: 39833913)
Nat Genet. 2011 Oct 02;43(11):1074-81. (PMID: 21964572)
Hum Genet. 2020 Nov;139(11):1417-1427. (PMID: 32488466)
Hum Mol Genet. 2011 May 15;20(10):1925-36. (PMID: 21349920)
Am J Med Genet. 1999 Feb 12;82(4):312-7. (PMID: 10051164)
Hum Mol Genet. 2009 Jun 15;18(12):2188-203. (PMID: 19324899)
Bioinformatics. 2018 Sep 15;34(18):3094-3100. (PMID: 29750242)
Bioinformatics. 2018 Mar 1;34(5):867-868. (PMID: 29096012)
Cytogenet Genome Res. 2021;161(5):225-226. (PMID: 34407535)
NPJ Genom Med. 2024 Dec 18;9(1):66. (PMID: 39695126)
Cell Genom. 2024 Jul 10;4(7):100590. (PMID: 38908378)
Nat Biotechnol. 2011 Jan;29(1):24-6. (PMID: 21221095)
Am J Med Genet A. 2023 Jul;191(7):1889-1899. (PMID: 37129290)
Nat Genet. 1993 Jul;4(3):252-5. (PMID: 8358433)
Entry Date(s): Date Created: 20260704 Date Completed: 20260704 Latest Revision: 20260813
Update Code: 20260814
PubMed Central ID: PMC13332952
DOI: 10.1007/s00439-026-02855-0
PMID: 42400701
Βάση Δεδομένων: MEDLINE
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  Data: Long-read genome sequencing resolves a de novo complex 18q12.1q21.2 triplication causing partial tetrasomy and reveals its underlying mechanism.
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  Data: <searchLink fieldCode="AU" term="%22Redaelli+S%22">Redaelli S</searchLink>; School of Medicine and Surgery, University of Milano-Bicocca, Monza, 20900, Italy.<br /><searchLink fieldCode="AU" term="%22Tritto+V%22">Tritto V</searchLink>; Department of Medical Biotechnology and Translational Medicine (BIOMETRA), University of Milan, Milan, 20122, Italy.<br /><searchLink fieldCode="AU" term="%22Mangano+E%22">Mangano E</searchLink>; Institute for Biomedical Technologies (ITB), National Research Council (CNR), Segrate, 20054, Italy.<br /><searchLink fieldCode="AU" term="%22Bordoni+R%22">Bordoni R</searchLink>; Institute for Biomedical Technologies (ITB), National Research Council (CNR), Segrate, 20054, Italy.<br /><searchLink fieldCode="AU" term="%22Sala+E%22">Sala E</searchLink>; UC Medical Genetics, Fondazione IRCCS San Gerardo dei Tintori, Monza, 20900, Italy.<br /><searchLink fieldCode="AU" term="%22Villa+N%22">Villa N</searchLink>; UC Medical Genetics, Fondazione IRCCS San Gerardo dei Tintori, Monza, 20900, Italy.<br /><searchLink fieldCode="AU" term="%22Crosti+F%22">Crosti F</searchLink>; UC Medical Genetics, Fondazione IRCCS San Gerardo dei Tintori, Monza, 20900, Italy.<br /><searchLink fieldCode="AU" term="%22Dalprà+L%22">Dalprà L</searchLink>; School of Medicine and Surgery, University of Milano-Bicocca, Monza, 20900, Italy.; UC Medical Genetics, Fondazione IRCCS San Gerardo dei Tintori, Monza, 20900, Italy.<br /><searchLink fieldCode="AU" term="%22Spaccini+L%22">Spaccini L</searchLink>; Clinical Genetics Unit, Department of Obstetrics and Gynecology, Vittore Buzzi Children's Hospital, University of Milan, Milan, 20122, Italy.<br /><searchLink fieldCode="AU" term="%22Sirtori+A%22">Sirtori A</searchLink>; Scuola di Specializzazione in Genetica Medica, University of Milano-Bicocca, Monza, 20900, Italy.<br /><searchLink fieldCode="AU" term="%22Cazzaniga+G%22">Cazzaniga G</searchLink>; School of Medicine and Surgery, University of Milano-Bicocca, Monza, 20900, Italy.; UC Medical Genetics, Fondazione IRCCS San Gerardo dei Tintori, Monza, 20900, Italy.<br /><searchLink fieldCode="AU" term="%22Conconi+D%22">Conconi D</searchLink>; School of Medicine and Surgery, University of Milano-Bicocca, Monza, 20900, Italy.<br /><searchLink fieldCode="AU" term="%22Bentivegna+A%22">Bentivegna A</searchLink>; School of Medicine and Surgery, University of Milano-Bicocca, Monza, 20900, Italy. angela.bentivegna@unimib.it.; UC Medical Genetics, Fondazione IRCCS San Gerardo dei Tintori, Monza, 20900, Italy. angela.bentivegna@unimib.it.<br /><searchLink fieldCode="AU" term="%22Riva+P%22">Riva P</searchLink>; Department of Medical Biotechnology and Translational Medicine (BIOMETRA), University of Milan, Milan, 20122, Italy. paola.riva@unimi.it.
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  Data: Chromosomal triplications are rare structural variations often associated with complex phenotypes. We report the molecular characterization of a novel intrachromosomal triplication at 18q12.1q21.2 identified in a fetus with ultrasound abnormalities. Conventional karyotyping and array-CGH revealed a partial tetrasomy and a 26 Mb region of loss of homozygosity (LOH), extending from the triplication to the telomere. Long-read sequencing (LRS) identified breakpoint junctions revealing a direct-inverted-direct triplication structure. Breakpoint analysis suggested that this rearrangement arose through a U-type exchange between sister chromatids, likely mediated by microhomology-based mechanisms. This process likely generated a transient dicentric chromosome that subsequently broke during mitosis. The resulting duplicated chromosome may have been stabilized by telomere capture, consistent with the triplicated 18q12.1q21.2 region followed by the 18q21.2q23 LOH. Nine genes within the triplicated region, including SMAD2 and SMAD4, showed high predicted sensitivity to increased dosage, possibly contributing to the clinical phenotype. This study highlights the utility of LRS in defining complex chromosomal rearrangements and emphasizes the importance of molecular breakpoint analysis for understanding pathogenic mechanisms and improving genetic prenatal diagnosis.<br /> (© 2026. The Author(s).)
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  Data: Declarations. Conflict of interest: The authors declare no competing interests. Ethical approval: We followed the guidelines of the ethics committee of the Fondazione IRCCS San Gerardo dei Tintori, Monza. Consent to participate: Informed consent was obtained from parents’ participants included in the study. Consent for publication: Participants signed informed consent regarding publishing the data.
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  Data: Front Cell Dev Biol. 2022 Mar 22;10:825345. (PMID: <searchLink fieldCode="PM" term="%2235392164%22">35392164)</searchLink><br />Am J Med Genet A. 2024 Mar;194(3):e63457. (PMID: <searchLink fieldCode="PM" term="%2237881147%22">37881147)</searchLink><br />Nat Rev Genet. 2016 Apr;17(4):224-38. (PMID: <searchLink fieldCode="PM" term="%2226924765%22">26924765)</searchLink><br />Genome Med. 2025 Jan 20;17(1):6. (PMID: <searchLink fieldCode="PM" term="%2239833913%22">39833913)</searchLink><br />Nat Genet. 2011 Oct 02;43(11):1074-81. (PMID: <searchLink fieldCode="PM" term="%2221964572%22">21964572)</searchLink><br />Hum Genet. 2020 Nov;139(11):1417-1427. (PMID: <searchLink fieldCode="PM" term="%2232488466%22">32488466)</searchLink><br />Hum Mol Genet. 2011 May 15;20(10):1925-36. (PMID: <searchLink fieldCode="PM" term="%2221349920%22">21349920)</searchLink><br />Am J Med Genet. 1999 Feb 12;82(4):312-7. (PMID: <searchLink fieldCode="PM" term="%2210051164%22">10051164)</searchLink><br />Hum Mol Genet. 2009 Jun 15;18(12):2188-203. (PMID: <searchLink fieldCode="PM" term="%2219324899%22">19324899)</searchLink><br />Bioinformatics. 2018 Sep 15;34(18):3094-3100. (PMID: <searchLink fieldCode="PM" term="%2229750242%22">29750242)</searchLink><br />Bioinformatics. 2018 Mar 1;34(5):867-868. (PMID: <searchLink fieldCode="PM" term="%2229096012%22">29096012)</searchLink><br />Cytogenet Genome Res. 2021;161(5):225-226. (PMID: <searchLink fieldCode="PM" term="%2234407535%22">34407535)</searchLink><br />NPJ Genom Med. 2024 Dec 18;9(1):66. (PMID: <searchLink fieldCode="PM" term="%2239695126%22">39695126)</searchLink><br />Cell Genom. 2024 Jul 10;4(7):100590. (PMID: <searchLink fieldCode="PM" term="%2238908378%22">38908378)</searchLink><br />Nat Biotechnol. 2011 Jan;29(1):24-6. (PMID: <searchLink fieldCode="PM" term="%2221221095%22">21221095)</searchLink><br />Am J Med Genet A. 2023 Jul;191(7):1889-1899. (PMID: <searchLink fieldCode="PM" term="%2237129290%22">37129290)</searchLink><br />Nat Genet. 1993 Jul;4(3):252-5. (PMID: <searchLink fieldCode="PM" term="%228358433%22">8358433)</searchLink>
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