Detection using QMPSF of partial deletions and duplication of the NSD1 gene in Sotos syndrome. P. Saugier-Veber1, C. Coubes2, M. Holder3, V. Drouin-Garraud1, J. Roume4, D. Bonneau5, S. Férenbach1, T. Frebourg1, L. Burglen6. 1) Department of Genetics, University Hospital, Rouen, France; 2) Department of Medical Genetics, University Hospital, Montpellier, France; 3) Department of Medical Genetics, University Hospital, Lille, France; 4) Department of Medical Genetics, Hospital of Poissy-Saint Germain en Laye, Poissy, France; 5) Department of Medical Genetics, University Hospital, Angers, France; 6) Department of Genetics, Trousseau Hospital, Paris, France.
Sotos syndrome is an overgrowth syndrome characterized by pre- and postnatal overgrowth with advanced bone age, macrocephaly, characteristic facial features and variable mental retardation. Large 5q35 microdeletions encompassing the NSD1 gene detected by FISH, and intragenic NSD1 mutations have been reported in 60-90 % Sotos patients and in some patients affected with Weaver syndrome. We and others recently reported partial deletions of the NSD1 gene. We have now developed a QMPSF (Quantitative Multiplex PCR of Short Fluorescent Fragments) assay covering exons 2 to 23 of the NSD1 gene and have integrated this QMPSF assay in the molecular diagnosis of Sotos syndrome. This QMPSF assay allowed us to identify 4 partial NSD1 deletions removing exon 2, exons 6-7-8, exons 18-19 and exons 22-23 and the first partial duplication of NSD1, involving exon 4. All patients exhibited characteristic features of Sotos syndrome and cannot be distinguished from patients with point NSD1 mutations. These results highlight the importance of systematic detection of such genomic rearrangements in the molecular diagnosis of Sotos syndrome by using molecular methods such as QMPSF since these NSD1 genomic rearrangements cannot be detected by FISH. From our experience, we estimate that the partial deletions and duplications represent 5 % of the NSD1 alterations whereas complete NSD1 deletions represent 12.5 % of the NSD1 alterations.