Sotos syndrome is cased by haploinsufficiency of the NSD1 gene. N. Kurotaki^1,2, N. Harada^1,2, N. Niikawa^1,2, N. Matsumoto^1,2. 1) Dept Human Genetics, Nagasaki Univ Sch, Nagasaki, Japan; 2) CREST, Japan Science and Technology Corporation, Kawaguchi, Japan.

   Sotos syndrome (SS, cerebral gigantism, OMIM *117550) is a neurological disorder characterized by prenatal-childhood overgrowth with advanced bone age, a peculiar face with large skull, acromegalic features and pointed chin, occasional brain anomalies and seizures, and mental retardation. SS patients were estimated to have a 3.9 % risk of benign and/or malignant tumors. We isolated the NSD1 gene from the 5q35 breakpoint of a patient with a de novo balanced translocation, t(5;8)(q35;q24.1) by positional cloning. NSD1 encodes 2,696 amino acids with SET, PHD finger, and PWWP domains, and may interact with nuclear receptors (NRs). It is expressed in the fetal and adult brain, kidney, skeletal muscle, spleen, and the thymus, and faintly in the lung. Among 42 SS patients examined, we detected 4 (10 %) de novo point mutations in NSD1, including a nonsense mutation (1310C->G, S437X), a one-bp deletion (3536delA), a one-bp insertion (5998insT), and a splice-donor-site mutation (6151+1G->A). In addition, FISH analysis using BAC clones flanking the 5q35 breakpoint revealed submicroscopic deletions involving the entire NSD1 gene in 20 (67%) of 30 patients whose chromosomes were available (Nat Genet 30:365-366, 2002). These results indicate that haploinsufficiency of NSD1 is the major cause of Sotos syndrome. We are analyzing additional 31 SS patients. Novel point mutations and deletions will be presented.