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Clin Genet. 2017 Jan;91(1):73-78. doi: 10.1111/cge.12803. Epub 2016 Jun 30.

NSD1 duplication in Silver-Russell syndrome (SRS): molecular karyotyping in patients with SRS features.

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Institute of Human Genetics, RWTH Aachen, Aachen, Germany.
II Department of Pediatrics, Semmelweis University, Budapest, Hungary.
Praxis für Humangenetik, Bremen, Germany.
Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University, Vilnius, Lithuania.
HSK Dr. Horst Schmidt Kliniken, Klinik für Kinder und Jugendliche, Wiesbaden, Germany.


Silver-Russell syndrome (SRS) is a growth retardation syndrome characterized by intrauterine and postnatal growth retardation, relative macrocephaly and protruding forehead, body asymmetry and feeding difficulties. Nearly 50% of cases show a hypomethylation in 11p15.5, in 10% maternal uniparental disomy of chromosome 7 is present. A significant number of patients with SRS features also exhibit chromosomal aberrations. We analyzed 43 individuals referred for SRS genetic testing by molecular karyotyping. Pathogenic variants could be detected in five of them, including a NSD1 duplication in 5q35 and a 14q32 microdeletion. NSD1 deletions are detectable in overgrowth disorders (Sotos syndrome and Beckwith-Wiedemann syndrome), whereas NSD1 duplications are associated with growth retardation. The 14q32 deletion is typically associated with Temple syndrome (TS14), but the identification of a patient in our cohort reflects the clinical overlap between TS14 and SRS. As determination of molecular subtypes is the basis for a directed counseling and therapy, the identification of pathogenic variants in >10% of the total cohort of patients referred for SRS testing and in >16% of characteristic individuals with the characteristic SRS phenotype confirms the need to apply molecular karyotyping in this cohort.


NSD1 duplication; Silver-Russell syndrome; Temple syndrome; copy number variations

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