Diagnostic Use of Genome Sequencing in Patients With 11p15.5 Imprinting Disorder Features: A Pilot Study.

Abstract

To assess the suitability of genome sequencing (GS) as the second step in the diagnostics of patients with the features of 11p15.5-associated imprinting disorders (ImpDis: Silver-Russell syndrome [SRS], Beckwith-Wiedemann syndrome [BWS]), we performed short-read GS in patients negatively tested for imprinting disturbances. Obtaining a genetic diagnosis for patients with the features of these syndromes is challenging due to the clinical and molecular heterogeneity and overlap, and many patients remain undiagnosed after the currently suggested stepwise diagnostic workup. GS was conducted in 48 patients (SRS features: n = 37 and BWS features: n = 11). The detection rate differed markedly between the ImpDis: although a genetic cause could be identified in 51% of patients referred with SRS features, no pathogenic variants were detected in patients with BWS features. Thus, GS substantially improves the diagnostic yield and broadens the spectrum of overlapping disorders with SRS features. Obtaining a precise molecular diagnosis provides the basis for a personalized clinical management. Our findings support the use of GS as a second-tier diagnostic tool for patients with growth disturbances, as it addresses all currently known variant types and shortens the diagnostic odyssey.