Deciphering a novel complex inversion affecting <i>F8</i> in a family with severe haemophilia A by optical genome mapping

Fahiminiya, Somayyeh; Oikonomopoulos, Spyros; Rivard, Georges‐Étienne; Gandhi, Mira; Scott, Patrick; Montpetit, Alexandre; Chen, Shu-Huang; Park, KyungHee; Vézina, Catherine; Ragoussis, Jiannis; Carvalho, Claudia M.B.; Mitchell, Grant A.; Soucy, Jean‐François; Gauthier, Julie

doi:10.1111/hae.14771

Cited by 2 publications

(2 citation statements)

References 14 publications

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“…To date, OGM has been successfully applied in mapping SVs associated with hematologic malignancies, hemophilia A, and other genetic diseases. 21,22 In this study, we combined OGM with long-distance polymerase chain reaction (LD-PCR) techniques to characterize the breakpoints of two severe HB patients with complete F9 gene deletion and three VTE patients with complete F9 duplication and triplication. Our findings reveal a shared duplication-triplication/inversion-duplication (DUP-TRP/INV-DUP) rearrangements, resulting in F9 duplication and triplication in two unrelated families.…”

Section: Introductionmentioning

confidence: 99%

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Complete F9 Gene Deletion, Duplication, and Triplication Rearrangements: Implications for Factor IX Expression and Clinical Phenotypes

Ma,

Li,

Sun

et al. 2023

Thromb Haemost

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Background Factor IX (FIX) plays a critical role in blood coagulation. Complete deletion of F9 results in severe hemophilia B, whereas the clinical implications of complete F9 duplication and triplication remain understudied. Objective To investigate the rearrangement mechanisms underlying complete F9 deletion (cases 1 and 2), duplication (cases 3 and 4), and triplication (case 5), and to explore their association with FIX expression levels and clinical impacts. Methods Plasma FIX levels were detected using antigen and activity assays. CNVplex technology, optical genome mapping, and long-distance polymerase chain reaction were employed to characterize the breakpoints of the chromosomal rearrangements. Results Cases 1 and 2 exhibited FIX activities below 1%. Case 3 displayed FIX activities within the reference range. However, cases 4 and 5 showed a significant increase in FIX activities. Alu-mediated nonallelic homologous recombination was identified as the cause of F9 deletion in case 1; FoSTeS/MMBIR (Fork Stalling and Template Switching/microhomology-mediated break-induced replication) contributed to both F9 deletion and tandem duplication observed in cases 2 and 3; BIR/MMBIR (break-induced replication/microhomology-mediated break-induced replication) mediated by the same pair of low-copy repeats results in similar duplication–triplication/inversion–duplication (DUP–TRP/INV–DUP) rearrangements in cases 4 and 5, leading to complete F9 duplication and triplication, respectively. Conclusion Large deletions involving the F9 gene exhibit no apparent pattern, and the extra-hematologic clinical phenotypes require careful analysis of other genes within the deletion. The impact of complete F9 duplication and triplication on FIX expression might depend on the integrity of the F9 upstream sequence and the specific rearrangement mechanisms. Notably, DUP–TRP/INV–DUP rearrangements significantly elevate FIX activity and are closely associated with thrombotic phenotypes.

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Section: Introductionmentioning

confidence: 99%

“…To date, OGM has been successfully applied in mapping SVs associated with hematologic malignancies, hemophilia A, and other genetic diseases. 21 22 …”

Section: Introductionmentioning

confidence: 99%

Complete F9 Gene Deletion, Duplication, and Triplication Rearrangements: Implications for Factor IX Expression and Clinical Phenotypes

Ma,

Li,

Sun

et al. 2023

Thromb Haemost

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Prenatal risk assessment of Xp21.1 duplication involving theDMDgene by optical genome mapping

Zhang,

Du,

Gao

et al. 2024

Life Sci. Alliance

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Structural variants (SVs) of unknown significance are great challenges for prenatal risk assessment, especially when involving dose-sensitive genes such asDMD. The pathogenicities of 5′-terminalDMDduplications in the database remain controversial. Four prenatal cases with Xp21.1 duplications were identified by routine prenatal genomic testing, encompassing the 5′-UTR to exons 1–2 in family 1 and family 2, and to exons 1–9 in family 3. The duplication in family 4 was non-contiguous covering the 5′-UTR to exon 1 and exons 3–7. All were traced to unaffected males in the family pedigrees. A new genome-wide approach of optical genome mapping was performed in families 1, 2, and 3 to delineate the breakpoints and orientation of the duplicated fragments. The extra copies were tandemly inserted into the upstream ofDMD, preserving the integrity of ORF from the second copy. The pathogenicities were thus reclassified as likely benign. Our data highlight the importance of structural delineation by optical genome mapping in prenatal risk assessment of incidentally identified SVs involvingDMDand other similar large dose-sensitive genes.

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Deciphering a novel complex inversion affecting F8 in a family with severe haemophilia A by optical genome mapping

Cited by 2 publications

References 14 publications

Complete F9 Gene Deletion, Duplication, and Triplication Rearrangements: Implications for Factor IX Expression and Clinical Phenotypes

Complete F9 Gene Deletion, Duplication, and Triplication Rearrangements: Implications for Factor IX Expression and Clinical Phenotypes

Prenatal risk assessment of Xp21.1 duplication involving theDMDgene by optical genome mapping

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