Unusual deletion of the maternal 11p15 allele in Beckwith\u2013Wiedemann syndrome with an impact on both imprinting domains

Thomas Eggermann,Lutz Pfeiffer,Matthias Begemann

doi:10.1186/s13148-021-01020-w

Thomas Eggermann, Lutz Pfeiffer + Show 1 more

Open Access

https://doi.org/10.1186/s13148-021-01020-w

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Abstract

BackgroundWhereas duplications in 11p15.5 covering both imprinting centers (ICs) and their subordinated genes account for up to 1% of Beckwith–Wiedemann and Silver–Russell syndrome patients (BWS, SRS), the deletions in 11p15.5 reported so far only affect one of the ICs. In these cases, not only the size and gene content had an impact on the phenotype, but also the sex of the contributing parent influences the clinical signs of the deletion carrier.ResultsWe here report on the first case with a heterozygous deletion within the maternal allele affecting genes which are regulated by both ICs in 11p15.5 in a BWS patient, and describe the molecular and clinical consequences in case of its maternal or paternal inheritance.ConclusionsThe identification of a unique deletion affecting both 11p15.5 imprinting domains in a BWS patient illustrates the complexity of the regulation mechanisms in these key imprinting regions.

Highlights

We here report on the first case with a heterozygous deletion affecting the maternally inherited allele and genes regulated by both imprinting centers (ICs) in 11p15.5 in a Beckwith– Wiedemann and Silver–Russell syndrome (BWS) patient, and describe the molecular and clinical consequences in case of its maternal or paternal inheritance
In a patient referred for routine molecular genetic testing for BWS, an unusual deletion within 11p15.5 was identified
Whereas recent reports describe patients in which only one of the two domains was affected and the disturbances had an impact on genes regulated by either the Imprinting center region 1 (IC1) or the Imprinting center region 2 (IC2), in our case, the disturbance of both regions has to be considered with respect to clinical significance and genetic counselling (Fig. 2)

Summary

Introduction

Whereas duplications in 11p15.5 covering both imprinting centers (ICs) and their subordinated genes account for up to 1% of Beckwith–Wiedemann and Silver–Russell syndrome patients (BWS, SRS), the deletions in 11p15.5 reported so far only affect one of the ICs. The two differentially methylated imprinting control regions 1 and 2 (IC1, IC2) regulate the monoallelic and parent-of-origin dependent expression of a cluster of imprinted genes on chromosome 11p15.5. Deletions in 11p15.5 are rare [6,7,8,9,10], and losses affecting both imprinting regions have not yet been reported [8, 11,12,13]. Duplications of different sizes account for up to 1% of BWS and SRS patients, and they are either restricted to one of the two ICs, or affect both (for review: [13]). We here report on the first case with a heterozygous deletion affecting the maternally inherited allele and genes regulated by both ICs in 11p15.5 in a BWS patient, and describe the molecular and clinical consequences in case of its maternal or paternal inheritance

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