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The Analysis of Variants in the General Population Reveals That PMM2 Is Extremely Tolerant to Missense Mutations and That Diagnosis of PMM2-CDG Can Benefit from the Identification of Modifiers
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Molecular and Clinical Opposite Findings in 11p15.5 Associated Imprinting Disorders: Characterization of Basic Mechanisms to Improve Clinical Management

Institute of Human Genetics, University Hospital, Technical University Aachen (RWTH), 52074 Aachen, Germany
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Int. J. Mol. Sci. 2019, 20(17), 4219; https://doi.org/10.3390/ijms20174219
Received: 5 July 2019 / Revised: 26 August 2019 / Accepted: 26 August 2019 / Published: 28 August 2019
(This article belongs to the Special Issue Rare Diseases: Molecular Mechanisms and Therapeutic Strategies)
Silver–Russell and Beckwith–Wiedemann syndromes (SRS, BWS) are rare congenital human disorders characterized by opposite growth disturbances. With the increasing knowledge on the molecular basis of SRS and BWS, it has become obvious that the disorders mirror opposite alterations at the same genomic loci in 11p15.5. In fact, these changes directly or indirectly affect the expression of IGF2 and CDKN1C and their associated pathways, and thereby, cause growth disturbances as key features of both diseases. The increase of knowledge has become possible with the development and implementation of new and comprehensive assays. Whereas, in the beginning molecular testing was restricted to single chromosomal loci, many tests now address numerous loci in the same run, and the diagnostic implementation of (epi)genome wide assays is only a question of time. These high-throughput approaches will be complemented by the analysis of other omic datasets (e.g., transcriptome, metabolome, proteome), and it can be expected that the integration of these data will massively improve the understanding of the pathobiology of imprinting disorders and their diagnostics. Especially long-read sequencing methods, e.g., nanopore sequencing, allowing direct detection of native DNA modification, will strongly contribute to a better understanding of genomic imprinting in the near future. Thereby, new genomic loci and types of pathogenic variants will be identified, resulting in more precise discrimination into different molecular subgroups. These subgroups serve as the basis for (epi)genotype–phenotype correlations, allowing a more directed prognosis, counseling, and therapy. By deciphering the pathophysiological consequences of SRS and BWS and their molecular disturbances, future therapies will be available targeting the basic cause of the disease and respective pathomechanisms and will complement conventional therapeutic strategies. View Full-Text
Keywords: genomic imprinting; Silver–Russell syndrome; Beckwith–Wiedemann syndrome; therapy genomic imprinting; Silver–Russell syndrome; Beckwith–Wiedemann syndrome; therapy
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Wesseler, K.; Kraft, F.; Eggermann, T. Molecular and Clinical Opposite Findings in 11p15.5 Associated Imprinting Disorders: Characterization of Basic Mechanisms to Improve Clinical Management. Int. J. Mol. Sci. 2019, 20, 4219.

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