One test for all: whole exome sequencing significantly improves the diagnostic yield in growth retarded patients referred for molecular testing for Silver\u2013Russell syndrome

Robert Meyer,Birute Burnyte,Gyorgy Fekete,Peter Kroisel,Christian Thomas Hübner,Stephanie Demuth,Carmen Schröder,Magdeldin Elgizouli,Daniela Dey,Thomas Opladen,Miriam Elbracht,Asmaa Kenawy,Thomas Eggermann,Ulrike Schara,Alma Kuechler,Matthias Begemann,Laima Ambrozaityte

doi:10.1186/s13023-021-01683-x

Abstract

BackgroundSilver-Russell syndrome (SRS) is an imprinting disorder which is characterised by severe primordial growth retardation, relative macrocephaly and a typical facial gestalt. The clinical heterogeneity of SRS is reflected by a broad spectrum of molecular changes with hypomethylation in 11p15 and maternal uniparental disomy of chromosome 7 (upd(7)mat) as the most frequent findings. Monogenetic causes are rare, but a clinical overlap with numerous other disorders has been reported. However, a comprehensive overview on the contribution of mutations in differential diagnostic genes to phenotypes reminiscent to SRS is missing due to the lack of appropriate tests. With the implementation of next generation sequencing (NGS) tools this limitation can now be circumvented.Main bodyWe analysed 75 patients referred for molecular testing for SRS by a NGS-based multigene panel, whole exome sequencing (WES), and trio-based WES. In 21/75 patients a disease-causing variant could be identified among them variants in known SRS genes (IGF2, PLAG1, HMGA2). Several patients carried variants in genes which have not yet been considered as differential diagnoses of SRS.ConclusionsWES approaches significantly increase the diagnostic yield in patients referred for SRS testing. Several of the identified monogenetic disorders have a major impact on clinical management and genetic counseling.

Highlights

Silver-Russell syndrome (SRS) is an imprinting disorder which is characterised by severe primordial growth retardation, relative macrocephaly and a typical facial gestalt
whole exome sequencing (WES) approaches significantly increase the diagnostic yield in patients referred for SRS testing
In our cohort of patients referred for SRS testing, we substantiate the need of next generation sequencing (NGS)-based assays in the molecular diagnostic workup in this heterogeneous cohort, and in agreement with findings from other heterogeneous disorders we show that the application of WES significantly improves the detection rate (21.41% versus 8.5% in the cohort analysed by Meyer et al [7]) for comparable hands-on time and costs

Summary

Introduction

Silver-Russell syndrome (SRS) is an imprinting disorder which is characterised by severe primordial growth retardation, relative macrocephaly and a typical facial gestalt. Up to 10% of SRS patients exhibit a maternal uniparental disomy of chromosome 7 (upd(7)mat), and a relevant number of patients carry alterations of chromosome 14q32 which are typically associated with Temple syndrome (TS14, OMIM#616222). Additional molecular alterations in SRS comprise less common genetic variants, i.e. UPDs of chromosome 20, diverse submicroscopic deletions and duplications (copy number variants, CNV) [4], and pathogenic variants in single genes. These molecular changes are either associated with typical SRS phenotypes (e.g. microdeletions in 12q14, pathogenic variants in IGF2, CDKN1C, PLAG1, HMGA2) [4,5,6], or with differential diagnoses of SRS (see [2])

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