Need for a precise molecular diagnosis in Beckwith-Wiedemann and Silver-Russell syndrome: what has to be considered and why it is important

Abstract

Molecular diagnostic testing of the 11p15.5-associated imprinting disorders Silver-Russell and Beckwith-Wiedemann syndrome (SRS, BWS) is challenging due to the broad spectrum of molecular defects and their mosaic occurrence. Additionally, the decision on the molecular testing algorithm is hindered by their clinical heterogeneity. However, the precise identification of the type of defect is often a prerequisite for the clinical management and genetic counselling. Four major molecular alterations (epimutations, uniparental disomies, copy number variants, single nucleotide variants) have been identified, but their frequencies vary between SRS and BWS. Due to their molecular aetiology, epimutations in both disorders as well as upd(11)pat in BWS are particular prone to mosaicism which might additionally complicate the interpretation of testing results. We report on our experience of molecular analysis in a total cohort of 1448 patients referred for diagnostic testing of BWS and SRS, comprising a dataset from 737 new patients and from 711 cases from a recent study. Though the majority of positively tested patients showed the expected molecular results, we identified a considerable number of clinically unexpected molecular alterations as well as not yet reported changes and discrepant mosaic distributions. Additionally, the rate of multilocus imprinting disturbances among the patients with epimutations and uniparental diploidies could be further specified. Altogether, these cases show that comprehensive testing strategies have to be applied in diagnostic testing of SRS and BWS. The precise molecular diagnosis is required as the basis for a targeted management (e.g. ECG (electrocardiogram) and tumour surveillance in BWS, growth treatment in SRS). The molecular diagnosis furthermore provides the basis for genetic counselling. However, it has to be considered that recurrence risk calculation is determined by the phenotypic consequences of each molecular alteration and mechanism by which the alteration arose. Key messages The detection rates for the typical molecular defects of Beckwith-Wiedemann syndrome or Silver-Russell syndrome (BWS, SRS) are lower in routine cohorts than in clinically well-characterised ones. A broad spectrum of (unexpected) molecular alterations in both disorders can be identified. Multilocus imprinting disturbances (MLID) are less frequent in SRS than expected. The frequency of MLID and uniparental diploidy in BWS is confirmed. Mosaicism is a diagnostic challenge in BWS and SRS. The precise determination of the molecular defects affecting is the basis for a targeted clinical management and genetic counselling.

Role of Imprinting Disorders in Short Children Born SGA and Silver-Russell Syndrome Spectrum

“…In our study, the frequency of MLID was 3.4% in the patients with various IDs, and 4.5% in patients with various IDs classified into the SRS-compatible group. Recently, Eggermann et al reported that the frequency of MLID was 3.6% in SRS patients with aberrant findings ( 39 ). These findings suggest that MLID in patients with SRS is less frequent.…”

Clinical and Molecular Diagnosis of Beckwith-Wiedemann Syndrome with Single- or Multi-Locus Imprinting Disturbance

“…MLID is not restricted to BWS, since it has been reported in other genomic imprinting diseases [ 22 ]. In BWS, MLID frequency is observed in 20–50% of patients with IC2 LOM [ 6 , 7 , 8 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ], while it is very rare among cases with IC1 GOM [ 33 ]. Recently, genome-wide epigenetic defects, comprising both imprinted and non-imprinted loci, have been identified in patients with clinical diagnosis of BWS not confirmed by molecular testing.…”

Microdeletions in 1q21 and 8q12.1 depict two additional molecular subgroups of Silver-Russell syndrome like phenotypes

“…Due to a lack of specificity of these symptoms, and clinical heterogeneity, SRS is often discussed being a differential diagnosis and is genetically tested in patients with growth retardation. Consequently, the detection rate for the currently known molecular disturbances of SRS is only 10–20% (averaged detection rate in different diagnostic centers (unpublished data, [ 2 ]), whereas in clinically well characterized cohorts of SRS patients it reaches nearly 70%.…”