Abstract
AbstractImprinting disorders are a group of rare diseases with a broad phenotypic spectrum caused by a wide variety of genetic and epigenetic disturbances of imprinted genes or gene clusters. The molecular genetic causes and their respective frequencies vary between the different imprinting disorders so that each has its unique requirements for the diagnostic workflow, making it challenging. To add even more complexity to this field, new molecular genetic causes have been identified over time and new technologies have enhanced the detectability e. g. of mosaic disturbances.The precise identification of the underlying molecular genetic cause is of utmost importance in regard to recurrence risk in the families, tumour risk, clinical management and conventional and in the future therapeutic managements.Here we give an overview of the imprinting disorders, their specific requirements for the diagnostic workup and the most common techniques used and point out possible pitfalls.
Highlights
Due to their molecular heterogeneity and the continuous reports on new molecular findings, diagnostic testing of imprinting disorders (ImpDis) is challenging and each entity shows a different pattern of molecular disturbances (Table 1)
MS multiplex ligation-dependent probe amplification (MS-MLPA) should be applied as first step analysis, as it allows the simultaneous detection of all three subtypes, and at least in Silver–Russell syndrome (SRS) and Beckwith–Wiedemann syndrome (BWS) imprinting defects can be discriminated from uniparental disomy (UPD)
MS assays commonly have the capacity to detect the methylation changes caused by copy number variations (CNVs), imprinting defects and UPDs affecting imprinted regions, though depending on the underlying technology and the chromosome analysed not all tests can discriminate between the different molecular subtypes
Summary
Due to their molecular heterogeneity and the continuous reports on new molecular findings, diagnostic testing of imprinting disorders (ImpDis) is challenging and each entity shows a different pattern of molecular disturbances (Table 1). The postzygotic origin of several molecular alterations re-
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