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

• DOI: 10.1186/s13023-021-01683-x
• Publication Date: 2021-01-22T07:03:21Z
• Authors: Robert Meyer; Matthias Begemann; Christian Thomas ...; Daniela Dey; Alma Kuechler; Magdeldin Elgizouli; Ulrike Schara; Laima Ambrozaityte; Birute Burnyte; Carmen Schröder; Asmaa Kenawy; Peter Kroisel; Stephanie Demuth; Gyorgy Fekete; Thomas Opladen; Miriam Elbracht; Thomas Eggermann
• Keywords: Exome sequencing; FOS: Computer and information sciences; Genetic testing; 10039 Institute of Medical Genetics; Medizin; Gene; Human genetics; Pathology; 2736 Pharmacology (medical); Macrocephaly; Diagnostic detection rate; Molecular genetics; 0303 health sciences; R; Life Sciences; 3. Good health; Targeted multigene panel NGS; Phenotype; Molecular Diagnostic Techniques; Medicine; Differential diagnosis; Trisomy Detection; 2716 Genetics (clinical); Bioinformatics; Karyotype; Epigenetic Modifications and Their Functional Implications; 610 Medicine & health; Chromosome; Clinical genetics and genomics ; Silver-Russell Syndrome/genetics [MeSH] ; Targeted multigene panel NGS ; Diagnostic detection rate ; Humans [MeSH] ; Molecular Diagnostic Techniques [MeSH] ; Whole Exome Sequencing [MeSH] ; Next generation sequencing ; Silver–Russell syndrome ; Silver-Russell Syndrome/diagnosis [MeSH] ; DNA Methylation [MeSH] ; Research ; Uniparental Disomy [MeSH] ; Whole exome sequencing ; Phenotype [MeSH]; Silver–Russell syndrome; 03 medical and health sciences; Next generation sequencing; Biochemistry, Genetics and Molecular Biology; Exome Sequencing; Health Sciences; Genetics; Humans; Molecular Biology; Biology; Research; Whole exome sequencing; Uniparental disomy; Prenatal Aneuploidy Diagnosis and Screening Techniques; DNA Methylation; Uniparental Disomy; Genomic Imprinting and Parental Gene Expression Control; Silver-Russell Syndrome; FOS: Biological sciences; Pediatrics, Perinatology and Child Health; 570 Life sciences; biology; Genetic counseling

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.