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.
