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- Baskin, Berivan, et al.
(författare)
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High frequency of copy number variations (CNVs) in the chromosome 11p15 region in patients with Beckwith-Wiedemann syndrome
- 2014
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Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 133:3, s. 321-330
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Tidskriftsartikel (refereegranskat)abstract
- Beckwith-Wiedemann syndrome (BWS), an overgrowth and tumor predisposition syndrome is clinically heterogeneous. Its variable presentation makes molecular diagnosis particularly important for appropriate counseling of patients with respect to embyronal tumor risk and recurrence risk. BWS is characterized by macrosomia, omphalocele, and macroglossia. Additional clinical features can include hemihyperplasia, embryonal tumors, umbilical hernia, and ear anomalies. BWS is etiologically heterogeneous arising from dysregulation of one or both of the chromosome 11p15.5 imprinting centers (IC) and/or imprinted growth regulatory genes on chromosome 11p15.5. Most BWS cases are sporadic and result from loss of maternal methylation at imprinting center 2 (IC2), gain of maternal methylation at imprinting center 1 (IC1) or paternal uniparental disomy (UPD). Heritable forms of BWS (15%) have been attributed mainly to mutations in the growth suppressor gene CDKN1C, but have also infrequently been identified in patients with copy number variations (CNVs) in the chromosome 11p15.5 region. Four hundred and thirty-four unrelated BWS patients referred to the molecular diagnostic laboratory were tested by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). Molecular alterations were detected in 167 patients, where 103 (62%) showed loss of methylation at IC2, 23 (14%) had gain of methylation at IC1, and 41 (25%) showed changes at both ICs usually associated with paternal UPD. In each of the three groups, we identified patients in whom the abnormalities in the chromosome 11p15.5 region were due to CNVs. Surprisingly, 14 patients (9%) demonstrated either deletions or duplications of the BWS critical region that were confirmed using comparative genomic hybridization (CGH) array analysis. The majority of these CNVs were associated with a methylation change at IC1. Our results suggest that CNVs in the 11p15.5 region contribute significantly to the etiology of BWS. We highlight the importance of performing deletion/duplication testing in addition to methylation analysis in the molecular investigation of BWS in order to improve our understanding of the molecular basis of this disorder, and to provide accurate genetic counselling.
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| 2. |
- Xu, Yu, et al.
(författare)
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An atlas of genetic scores to predict multi-omic traits
- 2023
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Ingår i: Nature. - : Springer Nature. - 0028-0836 .- 1476-4687. ; 616:7955, s. 123-131
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Tidskriftsartikel (refereegranskat)abstract
- The use of omic modalities to dissect the molecular underpinnings of common diseases and traits is becoming increasingly common. But multi-omic traits can be genetically predicted, which enables highly cost-effective and powerful analyses for studies that do not have multi-omics1. Here we examine a large cohort (the INTERVAL study2; n = 50,000 participants) with extensive multi-omic data for plasma proteomics (SomaScan, n = 3,175; Olink, n = 4,822), plasma metabolomics (Metabolon HD4, n = 8,153), serum metabolomics (Nightingale, n = 37,359) and whole-blood Illumina RNA sequencing (n = 4,136), and use machine learning to train genetic scores for 17,227 molecular traits, including 10,521 that reach Bonferroni-adjusted significance. We evaluate the performance of genetic scores through external validation across cohorts of individuals of European, Asian and African American ancestries. In addition, we show the utility of these multi-omic genetic scores by quantifying the genetic control of biological pathways and by generating a synthetic multi-omic dataset of the UK Biobank3 to identify disease associations using a phenome-wide scan. We highlight a series of biological insights with regard to genetic mechanisms in metabolism and canonical pathway associations with disease; for example, JAK-STAT signalling and coronary atherosclerosis. Finally, we develop a portal ( https://www.omicspred.org/ ) to facilitate public access to all genetic scores and validation results, as well as to serve as a platform for future extensions and enhancements of multi-omic genetic scores.
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