1. ¹Institut für Medizinische Genetik, Humboldt-Universität, Charité, Berlin, Germany
2. ²Max-Planck Institut für Molekulare Genetik, Berlin, Germany
3. ³Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany
4. ⁴Abteilung für Medizinische Genetik, Altonaer Kinderkrankenhaus, Hamburg, Germany
5. ⁵Institut für Humangenetik, Humboldt-Universität, Charité, Berlin, Germany
6. ⁶Klinik für Kinder und Jugendmedizin, Krankenhaus Lichtenberg, Berlin, Germany
7. ⁷Department of Internal Medicine, Division of Medical Genetics, Istanbul University, Turkey
8. ⁸Kinderzentrum München, Medizinische Genetik, München, Germany
9. ⁹Institut für Humangenetik und Anthropologie der Universität Düsseldorf, Germany
10. ¹⁰Institut für Humangenetik, Klinikum der Johann Wolfgang Goethe Universität, Frankfurt, Germany
11. ¹¹Institut für Humangenetik, Universitätsklinikum Lübeck, Lübeck, Germany
12. ¹²Institut für Klinische Genetik, Technische Universität, Dresden, Germany
13. ¹³Kinderärztliche Gemeinschaftpraxis, Bremen, Germany
14. ¹⁴Klinik für Kinderheilkunde und Jugendmedizin, Marienhospital Osnabrück, Osnabrück, Germany

Correspondence: S Mundlos, Institut für Medizinische Genetik, Humboldt-Universität, Charité, Augustenburger Platz 1, Berlin 13353, Germany. Tel: +49 (0)30 4505 69121; Fax: +49 (0)30 4505 69915; E-mail: stefan.mundlos@charite.de

Deceased.

Received 27 February 2003; Revised 29 April 2003; Accepted 7 May 2003.

Abstract

Recently, deletions encompassing the nuclear receptor binding SET-Domain 1 (NSD1) gene have been described as the major cause of Japanese patients with the Sotos syndrome, whereas point mutations have been identified in the majority of European Sotos syndrome patients. In order to investigate a possible phenotype–genotype correlation and to further define the predictive value of NSD1 mutations, we performed mutational analysis of the NSD1 gene in 20 patients and one familial case with Sotos syndrome, five patients with Weaver syndrome, six patients with unclassified overgrowth/mental retardation, and six patients with macrocephaly/mental retardation. We were able to identify mutations within the NSD1 gene in 18 patients and the familial case with Sotos syndrome (90%). The mutations (six nonsense, eight frame shifts, three splice site, one missense, one in-frame deletion) are expected to result in an impairment of NSD1 function. The best correlation between clinical assessment and molecular results was obtained for the Sotos facial gestalt in conjunction with overgrowth, macrocephaly, and developmental delay. In contrast to the high mutation detection rate in Sotos syndrome, none of the patients with Weaver syndrome, unclassified overgrowth/mental retardation and macrocephaly/mental retardation, harbored NSD1 mutations. We tested for large deletions by FISH analysis but were not able to identify any deletion cases. The results indicate that the great majority of patients with Sotos syndrome are caused by mutations in NSD1. Deletions covering the NSD1 locus were not found in the patients analyzed here.