Mosaic genome-wide maternal isodiploidy: an extreme form of imprinting disorder presenting as prenatal diagnostic challenge

Susanne Bens,Melanie Graf,Tanja Richter,Julia Kolarova,Manuel Luedeke,Krisztian Lato,Reiner Siebert,Gotthold Barbi,Thomas F Barth

doi:10.1186/s13148-017-0410-y

Abstract

BackgroundUniparental disomy of certain chromosomes are associated with a group of well-known genetic syndromes referred to as imprinting disorders. However, the extreme form of uniparental disomy affecting the whole genome is usually not compatible with life, with the exception of very rare cases of patients with mosaic genome-wide uniparental disomy reported in the literature.ResultsWe here report on a fetus with intrauterine growth retardation and malformations observed on prenatal ultrasound leading to invasive prenatal testing. By cytogenetic (conventional karyotyping), molecular cytogenetic (QF-PCR, FISH, array), and methylation (MS-MLPA) analyses of amniotic fluid, we detected mosaicism for one cell line with genome-wide maternal uniparental disomy and a second diploid cell line of biparental inheritance with trisomy X due to paternal isodisomy X. As expected for this constellation, we observed DNA methylation changes at all imprinted loci investigated.ConclusionsThis report adds new information on phenotypic outcome of mosaic genome-wide maternal uniparental disomy leading to an extreme form of multilocus imprinting disturbance. Moreover, the findings highlight the technical challenges of detecting these rare chromosome disorders prenatally.

Highlights

Uniparental disomy of certain chromosomes are associated with a group of well-known genetic syndromes referred to as imprinting disorders
Non-disjunction at meiosis I can result in heterodisomy and isodisomy while non-disjunction at meiosis II leads to isodisomy of those parts of the chromosome set not involved in homologous recombination [1, 3]
Based on the obtained results of all analyses, we came to the conclusion that the underlying genetic condition in the fetus resulted from a mosaicism for a diploid cell line with genome-wide maternal isodiploidy in combination with a diploid biparental cell line with an extra chromosome X derived from paternal isodisomy X

Summary

Introduction

Uniparental disomy of certain chromosomes are associated with a group of well-known genetic syndromes referred to as imprinting disorders. Apart from UPD, imprinting disorders can result from primary epimutation [7] The latter term in this context refers to a change in DNA methylation at the differentially methylated region (DMR) regulating the parent-of-origin specific gene expression without evidence for a genomic mutation in cis [7]. In these instances, the DNA methylation disturbance can affect more than one locus and is referred to as “multilocus imprinting disturbance” (MLID). The amount and combination of loci affected is highly heterogeneous and generally does not extend to all known imprinted regions

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