Tissue variations of mosaic genome-wide paternal uniparental disomy and phenotype of multi-syndromal congenital hyperinsulinism

Christesen, Henrik Thybo; Christensen, Linda; Löfgren, Åsa Mattsson; Brøndum‐Nielsen, Karen; Svensson, Johan; Brusgaard, Klaus; Samuelsson, Sofie; Elfving, Maria; Jonson, Tord; Grønskov, Karen; Rasmussen, Lars Melholt; Backman, Torbjörn; Hansen, Lars Kjærsgaard; Larsen, Annette Rønholt; Petersen, Henrik; Detlefsen, Sönke

doi:10.1016/j.ejmg.2019.02.004

Cited by 9 publications

(14 citation statements)

References 29 publications

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“…72,73 So far, over 20 cases have been described, of which only three showed maternal origin (GW-mUPD), 72,74,75 while the rest were all of paternal origin (GW-pUPD). [76][77][78] Consistent with clinical manifestations of digyny and diandry, the main feature of GW-mUPD observed during prenatal development is intrauterine growth retardation, while androgenetic/biparental mosaicism is associated with placental mesenchymal dysplasia. [79][80][81] As reviewed by Postema et al, 77 the predominant phenotype in GW-pUPD individuals seems to be Beckwith-Wiedemann syndrome (BWS) and many patients are predisposed to cancer.…”

Section: Chimerismmentioning

confidence: 82%

“…The maternal or paternal only cell lineage, coexist with a normal diploid biparental cell lineage 72,73 . So far, over 20 cases have been described, of which only three showed maternal origin (GW‐mUPD), 72,74,75 while the rest were all of paternal origin (GW‐pUPD) 76‐78 . Consistent with clinical manifestations of digyny and diandry, the main feature of GW‐mUPD observed during prenatal development is intrauterine growth retardation, while androgenetic/biparental mosaicism is associated with placental mesenchymal dysplasia 79‐81 .…”

Section: Introductionmentioning

confidence: 99%

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Genome‐wide abnormalities in embryos: Origins and clinical consequences

2021

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Ploidy or genome‐wide chromosomal anomalies such as triploidy, diploid/triploid mixoploidy, chimerism, and genome‐wide uniparental disomy are the cause of molar pregnancies, embryonic lethality, and developmental disorders. While triploidy and genome‐wide uniparental disomy can be ascribed to fertilization or meiotic errors, the mechanisms causing mixoploidy and chimerism remain shrouded in mystery. Different models have been proposed, but all remain hypothetical and controversial, are deduced from the developmental persistent genomic constitutions present in the sample studied and lack direct evidence. New single‐cell genomic methodologies, such as single‐cell genome‐wide haplotyping, provide an extended view of the constitution of normal and abnormal embryos and have further pinpointed the existence of mixoploidy in cleavage‐stage embryos. Based on those recent findings, we suggest that genome‐wide anomalies, which persist in fetuses and patients, can for a large majority be explained by a noncanonical first zygotic cleavage event, during which maternal and paternal genomes in a single zygote, segregate to different blastomeres. This process, termed heterogoneic division, provides an overarching theoretical basis for the different presentations of mixoploidy and chimerism.

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Section: Chimerismmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Genome‐wide abnormalities in embryos: Origins and clinical consequences

2021

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“…It has been suggested that significant overlap likely exists between mechanisms of tumorigenesis in liver and pancreas [46] supported pluripotent cells that contribute liver and pancreas tissues with possible trans-conversion between these two tissues [47]. Further research is needed to confirm whether HI does indeed influence cancer risk within BWSp patients as a variety of other tumor types was observed through our case series and in other reports [48][49][50]. We additionally identified a case report of a female infant with HI and NBL without features of BWS [51], representing a similar clinical 'picture' to the male patient (#21) we presented in the case series.…”

Section: Discussionmentioning

confidence: 55%

Characteristics Associated with Tumor Development in Individuals Diagnosed with Beckwith–Wiedemann Spectrum: Novel Tumor-(epi)Genotype-Phenotype Associations in the BWSp Population

Duffy

Getz

Hathaway

et al. 2021

Genes

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Beckwith–Wiedemann Spectrum (BWSp) is the most common epigenetic childhood cancer predisposition disorder. BWSp is caused by (epi)genetic changes affecting the BWS critical region on chromosome 11p15. Clinically, BWSp represents complex molecular and phenotypic heterogeneity resulting in a range of presentations from Classic BWS to milder features. The previously reported tumor risk based on Classic BWS cohorts is 8–10% and routine tumor screening has been recommended. This work investigated the tumor risk and correlation with phenotype within a cohort of patients from Classic BWS to BWSp using a mixed-methods approach to explore phenotype and epigenotype profiles associated with tumor development through statistical analyses with post-hoc retrospective case series review. We demonstrated that tumor risk across BWSp differs from Classic BWS and that certain phenotypic features are associated with specific epigenetic causes; nephromegaly and/or hyperinsulinism appear associated with cancer in some patients. We also demonstrated that prenatal and perinatal factors that are not currently part of the BWSp classification may factor into tumor risk. Additionally, blood testing results are not necessarily synonymous with tissue testing results. Together, it appears that the current understanding from Classic BWS of (epi)genetics and phenotype correlations with tumors is not represented in the BWSp. Further study is needed in this complex population.

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“…Low level mosaicism with tissue variations can be difficult to detect (Kalish et al 2013;Christesen et al 2020). Clinical features include placental mesenchymal dysplasia (PMD) and placentomegaly, BWSp, hyperinsulinism, capillary hemangiomas, elevated risk of cancer, and signs of mosaicisms like lateralized overgrowth (Kotzot 2008;Kalish et al 2013;Postema et al 2019;Sheppard et al 2019).…”

Section: Introductionmentioning

confidence: 99%

Double paternal uniparental isodisomy 7 and 15 presenting with Beckwith–Wiedemann spectrum features

Berland

Rustad

Bentsen

et al. 2021

Cold Spring Harb Mol Case Stud

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Here we describe for the first time double paternal uniparental isodisomy (iUPD) 7 and 15 in a baby boy with features in the Beckwith-Wiedemann syndrome spectrum (BWSp) (placentomegaly, hyperinsulinism, enlarged viscera, hemangiomas, and earlobe creases) in addition to conjugated hyperbilirubinemia. His phenotype was also reminiscent of genome-wide paternal uniparental isodisomy. We discuss the most likely origin of the UPDs; a maternal double monosomy 7 and 15 rescued by duplication of the paternal chromosomes after fertilization. So far, paternal UPD7 is not associated with an abnormal phenotype, while paternal UPD15 causes Angelman syndrome. Methylation analysis for other clinically relevant imprinting disorders, including BWSp, was normal. Therefore, we hypothesized that the double UPD affected other imprinted genes. To look for such effects, patient fibroblast RNA was isolated and analyzed for differential expression compared to six controls. We did not find apparent transcription differences in imprinted genes outside chromosomes 7 and 15 in patient fibroblast. PEG10 (7q21.3) was the only paternally imprinted gene on these chromosomes upregulated beyond double-dose expectation (6-fold). We speculate that a high PEG10 level could have a growth-promoting effect as his phenotype was not related to aberrations in BWS-locus on 11p15.5 after DNA, RNA, and methylation testing. However, many genes in gene sets associated with growth were upregulated. This case broadens the phenotypic spectrum of UPDs but did not show evidence of involvement of an imprinted gene network.

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Tissue variations of mosaic genome-wide paternal uniparental disomy and phenotype of multi-syndromal congenital hyperinsulinism

Cited by 9 publications

References 29 publications

Genome‐wide abnormalities in embryos: Origins and clinical consequences

Genome‐wide abnormalities in embryos: Origins and clinical consequences

Characteristics Associated with Tumor Development in Individuals Diagnosed with Beckwith–Wiedemann Spectrum: Novel Tumor-(epi)Genotype-Phenotype Associations in the BWSp Population

Double paternal uniparental isodisomy 7 and 15 presenting with Beckwith–Wiedemann spectrum features

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