One test for all: whole exome sequencing significantly improves the diagnostic yield in growth retarded patients referred for molecular testing for Silver–Russell syndrome
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Published:2021-01-22
Issue:1
Volume:16
Page:
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ISSN:1750-1172
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Container-title:Orphanet Journal of Rare Diseases
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language:en
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Short-container-title:Orphanet J Rare Dis
Author:
Meyer Robert, Begemann Matthias, Hübner Christian Thomas, Dey Daniela, Kuechler Alma, Elgizouli Magdeldin, Schara Ulrike, Ambrozaityte Laima, Burnyte Birute, Schröder Carmen, Kenawy Asmaa, Kroisel Peter, Demuth Stephanie, Fekete Gyorgy, Opladen Thomas, Elbracht Miriam, Eggermann ThomasORCID
Abstract
Abstract
Background
Silver-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 body
We 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.
Conclusions
WES 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.
Funder
Deutsche Forschungsgemeinschaft Projekt DEAL
Publisher
Springer Science and Business Media LLC
Subject
Pharmacology (medical),Genetics(clinical),General Medicine
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