RESEARCH ARTICLE Extending the Phenotype of Monosomy 1p36 Syndrome and Mapping of a Critical Region for Obesity and Hyperphagia Carla S. D’Angelo, 1 * Ilana Kohl, 1 Monica Castro Varela, 1 Cl audia I.E. de Castro, 1 Chong A. Kim, 2 D ebora R. Bertola, 2 Charles M. Lourenc ¸o, 3 and C elia P. Koiffmann 1 1 Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of S~ ao Paulo, S~ ao Paulo, Brazil 2 Genetics Unit, Department of Pediatrics, Children Institute, School of Medicine, University of S~ ao Paulo, S~ ao Paulo, Brazil 3 Neurogenetics Unit, Department of Medical Genetics, School of Medicine, University of S~ ao Paulo, Ribeir~ ao Preto, Brazil Received 20 May 2009; Accepted 28 September 2009 Rearrangements of 1p36 are the most frequently detected abnormalities in diagnostic testing for chromosomal cryptic imbalances and include variably sized simple terminal deletions, derivative chromosomes, interstitial deletions, and complex rearrangements. These rearrangements result in the specific pattern of malformation and neurodevelopmental disabilities that characterizes monosomy 1p36 syndrome. Thus far, no individual gene within this region has been conclusively deter- mined to be causative of any component of the phenotype. Nor is it known if the rearrangements convey phenotypes via a haploinsufficiency mechanism or through a position effect. We have used multiplex ligation-dependent probe amplification to screen for deletions of 1p36 in a group of 154 hyperphagic and overweight/obese, PWS negative individuals, and in a separate group of 83 patients initially sent to investigate a variety of other conditions. The strategy allowed the identification and delinea- tion of rearrangements in nine subjects with a wide spectrum of clinical presentations. Our work reinforces the association of monosomy 1p36 and obesity and hyperphagia, and further suggests that these features may be associated with non-classical manifestations of this disorder in addition to a submicroscopic deletion of 2–3 Mb in size. Multiplex ligation probe amplifica- tion using the monosomy 1p36 syndrome-specific kit coupled to the subtelomeric kit is an effective approach to identify and delineate rearrangements at 1p36. Ó 2009 Wiley-Liss, Inc. Key words: monosomy 1p36; MLPA; obesity; hyperphagia INTRODUCTION Constitutional rearrangements of 1p36 are the most common clinically significant chromosomal abnormalities detected in diag- nostic laboratories testing for cryptic imbalances in subtelomeres and other targeted genomic regions [Ravnan et al., 2006; Ballif et al., 2007; Shaffer et al., 2007]. Deletion of the subtelomeric region of 1p36 causes a constellation of characteristic clinical features in- cluding cognitive impairment and a specific facial appearance [Shapira et al., 1997; Gajecka et al., 2007; Battaglia et al., 2008], which is now recognized as the most common terminal deletion syndrome, given the estimated incidence of 1 in 5,000 [Heilstedt et al., 2003a]. Language skills are commonly delayed and expressive language is normally absent. The facial characteristics include straight eyebrows, deep-set eyes, midface hypoplasia, broad and flat nasal root/bridge, long philtrum, and pointed chin. The four classes of rearrangements identified in individuals with monosomy 1p36 in order of frequency are apparently pure/simple terminal deletions (67%), derivative chromosomes (16%), inter- stitial deletions (10%), and complex rearrangements (7%) [Gajecka Additional supporting information may be found in the online version of this article. Grant sponsor: State of S~ ao Paulo Research Foundation, FAPESP; Grant number: 04/10380-6; Grant sponsor: Centers for Research, Innovation and Diffusion, CEPID-FAPESP; Grant number: 1998/14254-2; Grant sponsor: The National Council for Scientific and Technological Development, CNPq; Grant number: 304381/2007-1. *Correspondence to: Carla S. D’Angelo, Departamento de Gen etica e Biologia Evolutiva, Centro de Estudos do Genoma Humano, Instituto de Bioci ^ encias, Universidade de S~ ao Paulo, Rua do Mat~ ao 277, sala 204/209 CEP 05508-900, S~ ao Paulo, SP, Brazil. E-mail: cdangelo@ib.usp.br Published online 22 December 2009 in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/ajmg.a.33160 How to Cite this Article: D’Angelo CS, Kohl I, Varela MC, de Castro CIE, Kim CA, Bertola DR, Lourenc ¸o CM, Koiffmann CP. 2010. Extending the phenotype of monosomy 1p36 syndrome and mapping of a critical region for obesity and hyperphagia. Am J Med Genet Part A 152A:102–110. Ó 2009 Wiley-Liss, Inc. 102