RESEARCH ARTICLE The Phenotypic Spectrum of Duplication 5q35.2–q35.3 Encompassing NSD1: Is It Really a Reversed Sotos Syndrome? Nicola Dikow, 1 * Bianca Maas, 1 Harald Gaspar, 2 Martina Kreiss-Nachtsheim, 3 Hartmut Engels, 3 Alma Kuechler, 4 Lutz Garbes, 5 Christian Netzer, 5 Teresa M. Neuhann, 6 Udo Koehler, 6 Kristina Casteels, 7 Koen Devriendt, 7 Johannes W.G. Janssen, 1 Anna Jauch, 1 Katrin Hinderhofer, 1 and Ute Moog 1 1 Institute of Human Genetics, Heidelberg University, Heidelberg, Germany 2 Institute of Human Genetics, Freiburg Medical Center, Freiburg, Germany 3 Institute of Human Genetics, University of Bonn, Bonn, Germany 4 Institut fu ¨r Humangenetik, Universita ¨tsklinikum Essen, Essen, Germany 5 Institute of Human Genetics, University of Cologne, Cologne, Germany 6 MGZ—Medizinisch Genetisches Zentrum, Munich, Germany 7 University Hospitals Leuven and Department Development and Regeneration, KU Leuven, Belgium Manuscript Received: 6 December 2012; Manuscript Accepted: 15 April 2013 Loss-of-function mutations of NSD1 and 5q35 microdeletions encompassing NSD1 are a major cause of Sotos syndrome (Sos), which is characterized by overgrowth, macrocephaly, character- istic facies, and variable intellectual disability (ID). Microdupli- cations of 5q35.2–q35.3 including NSD1 have been reported in only five patients so far and described clinically as a reversed Sos resulting from a hypothetical gene dosage effect of NSD1. Here, we report on nine patients from five families with interstitial duplication 5q35 including NSD1 detected by molecular karyo- typing. The clinical features of all 14 individuals are reviewed. Patients with microduplications including NSD1 appear to have a consistent phenotype consisting of short stature, microcephaly, learning disability or mild to moderate ID, and distinctive facial features comprising periorbital fullness, short palpebral fissures, a long nose with broad or long nasal tip, a smooth philtrum and a thin upper lip vermilion. Behavioral problems, ocular and minor hand anomalies may be associated. Based on our findings, we discuss the possible etiology and conclude that it is possible, but so far unproven, that a gene dosage effect of NSD1 may be the major cause. Ó 2013 Wiley Periodicals, Inc. Key words: microduplication 5q35; NSD1; partial trisomy 5q; gene dosage; Sotos syndrome INTRODUCTION Since the advent of molecular karyotyping, pure microduplications of distal 5q have been rarely detected, even when taking into account both interstitial and terminal duplications [Witters et al., 1998; Zahnleiter et al., 2011]. This paper focuses on pure interstitial duplications 5q35.2–q35.3 containing the NSD1 gene. Loss-of- function mutations of NSD1 including deletions cause Sotos syn- drome (Sos, OMIM 117550) which is a well-known syndrome characterized predominantly by childhood overgrowth, macro- cephaly, typical facial features and learning disability [Tatton- Brown et al., 2005]. In contrast, microduplications involving 5q35.3 have been reported in only five cases so far and seem to be associated with short stature and microcephaly [Chen How to Cite this Article: Dikow N, Maas B, Gaspar H, Kreiss- Nachtsheim M, Engels H, Kuechler A, Garbes L, Netzer C, Neuhann TM, Koehler U, Casteels K, Devriendt K, Janssen JWG, Jauch A, Hinderhofer K, Moog U. 2013. The phenotypic spectrum of duplication 5q35.2–q35.3 encompassing NSD1: Is it really a reversed Sotos syndrome? Am J Med Genet Part A 161A:2158–2166. Conflict of interest: The authors declare no conflict of interest.  Correspondence to: Nicola Dikow, Institute of Human Genetics, INF 366, 69120 Heidelberg, Germany. E-mail: nicola.dikow@med.uni-heidelberg.de Article first published online in Wiley Online Library (wileyonlinelibrary.com): 2 August 2013 DOI 10.1002/ajmg.a.36046 Ó 2013 Wiley Periodicals, Inc. 2158