A late onset sickle cell disease reveals a mosaic segmental uniparental isodisomy of chromosome 11p15

Vinatier, Isabelle; Martín, Xavier Brisset; Costa, J Da; Bazin, Anne; Giraudier, Stéphane; Joly, Philippe

doi:10.1016/j.bcmd.2014.07.021

Cited by 4 publications

(3 citation statements)

References 9 publications

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“…In addition, there appears to be a potential selective growth advantage of blood cells with patUPD of 11p15. 22 That is, some patients may, as they age, have an increase in the proportion of cells in blood with patUPD. Therefore, both the timing of tissue sampling and the actual tissue sampled may influence the testing outcome.…”

Section: Discussionmentioning

confidence: 99%

Wilms tumour in Beckwith–Wiedemann Syndrome and loss of methylation at imprinting centre 2: revisiting tumour surveillance guidelines

et al. 2017

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Beckwith-Wiedemann Syndrome (BWS) is an overgrowth syndrome caused by a variety of molecular changes on chromosome 11p15.5. Children with BWS have a significant risk of developing Wilms tumours with the degree of risk being dependent on the underlying molecular mechanism. In particular, only a relatively small number of children with loss of methylation at the centromeric imprinting centre (IC2) were reported to have developed Wilms tumour. Discontinuation of tumour surveillance for children with BWS and loss of methylation at IC2 has been proposed in several recent publications. We report here three children with BWS reported to have loss of methylation at IC2 on clinical testing who developed Wilms tumour or precursor lesions. Using multiple molecular approaches and multiple tissues, we reclassified one of these cases to paternal uniparental disomy for chromosome 11p15.5. These cases highlight the current challenges in definitively assigning tumour risk based on molecular classification in BWS. The confirmed cases of loss of methylation at IC2 also suggest that the risk of Wilms tumour in this population is not as low as previously thought. Therefore, we recommend that for now, all children with a clinical or molecular diagnosis of BWS be screened for Wilms tumour by abdominal ultrasonography until the age of eight years regardless of the molecular classification.

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Section: Discussionmentioning

confidence: 99%

Wilms tumour in Beckwith–Wiedemann Syndrome and loss of methylation at imprinting centre 2: revisiting tumour surveillance guidelines

et al. 2017

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“…In-depth DNA analysis revealed that post-zygotic mitotic recombination had occurred, leading to mosaic segmental isodisomy. 57,58 These individuals had dual populations of HbSS and HbAS erythroid progenitors and peripheral red blood cells, with HbSS erythrocytes accounting for the chronic hemolytic phenotype of SCD.…”

Section: Molecular Factors Worsening the Hbas Phenotypementioning

confidence: 99%

The carrier state for sickle cell disease is not completely harmless

Thein

2019

Haematologica

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“…This may suggest that cell and tissue restricted segmental UPD are not rare somatic genetic events in pancreatic and possibly in other tissues. In fact, late onset ß-thalassemia and sickle cell anemia are other diseases with a similar mechanism of mosaic segmental paternal isodisomy at 11p15 unmasking a pathogenic variant in the HBB gene followed by clonal selection of hematopoetic progenitor cells due to enhanced proliferation (29,30).…”

Section: Discussionmentioning

confidence: 99%

Integration of genomic analysis and transcript expression of ABCC8 and KCNJ11 in focal form of congenital hyperinsulinism

Wieland

Schanze²,

Felgendreher³

et al. 2022

Front. Endocrinol.

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BackgroundThe focal form of CHI is caused by an autosomal recessive pathogenic variant affecting the paternal homologue of genes ABCC8 or KCNJ11 and a second somatic event specifically occurring in the affected islet of Langerhans. The approach of this study was to integrate the genetic changes occurring in pancreatic focal lesions of CHI at the genomic and transcriptional level.Research Design and MethodsPatients receiving therapeutic surgery and with proven ABCC8 or KCNJ11 pathogenic variants were selected and analyzed for loss of heterozygosity (LOH), changes in copy number and uniparental disomy (UPD) on the short am of chromosome 11 by molecular microarray analysis and methylation-specific MLPA. Gene expression was analyzed by RT-PCR and Massive Analysis of cDNA Ends (MACE).ResultsBoth genes, ABCC8 and KCNJ11, are located in proximity to the Beckwith-Wiedemann (BWS) imprinting control region on chromosome 11p15. Somatic paternal uniparental isodisomy (UPD) at chromosome 11p was identified as second genetic event in focal lesions resulting in LOH and monoallelic expression of the mutated ABCC8/KCNJ11 alleles. Of five patients with samples available for microarray analysis, the breakpoints of UPD on chromosome 11p were different. Samples of two patients were analyzed further for changes in gene expression. Profound downregulation of growth suppressing genes CDKN1 and H19 was detected in focal lesions whereas growth promoting gene ASCL2 and pancreatic transcription factors of the endocrine cell lineage were upregulated.ConclusionsPaternal UPD on the short arm of chromosome 11 appears to be the major second genetic event specifically within focal lesions of CHI but no common breakpoint for UDP can be delineated. We show for the first time upregulation of growth promoting ASCL2 (achaete-scute homolog 2) suggestive of a driving factor in postnatal focal expansion in addition to downregulation of growth suppressing genes CDKN1C and H19.

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A late onset sickle cell disease reveals a mosaic segmental uniparental isodisomy of chromosome 11p15

Cited by 4 publications

References 9 publications

Wilms tumour in Beckwith–Wiedemann Syndrome and loss of methylation at imprinting centre 2: revisiting tumour surveillance guidelines

Wilms tumour in Beckwith–Wiedemann Syndrome and loss of methylation at imprinting centre 2: revisiting tumour surveillance guidelines

The carrier state for sickle cell disease is not completely harmless

Integration of genomic analysis and transcript expression of ABCC8 and KCNJ11 in focal form of congenital hyperinsulinism

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