CLINICAL REPORT A 15q13.3 Homozygous Microdeletion Associated With a Severe Neurodevelopmental Disorder Suggests Putative Functions of the TRPM1, CHRNA7, and Other Homozygously Deleted Genes Jean-Baptiste LePichon, 1 Douglas C. Bittel, 2 William D. Graf, 1 and Shihui Yu 3 * 1 Section of Neurology, Children’s Mercy Hospitals and Clinics, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri 2 Section of Genetics and Molecular Medicine, Children’s Mercy Hospitals and Clinics, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri 3 Department of Pathology, Children’s Mercy Hospitals and Clinics, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri Received 9 September 2009; Accepted 24 December 2009 We identified a novel homozygous 15q13.3 microdeletion in a young boy with a complex neurodevelopmental disorder char- acterized by severe visual impairment, hypotonia, profound intellectual disability, and refractory epilepsy. The homozygous deletion of the genes within this deleted region provides a useful insight into the pathogenesis of the observed clinical phenotype. Absence of the Transient Receptor Potential Cation Channel, Subfamily M, Member 1 (TRPM1) gene product is proposed as a possible mechanism for the severe visual impairment; absence of CHRNA7 (alpha7-nicotinic receptor subunit) as a cause of the refractory seizures and severe cognitive impairment; and dele- tion of MTMR10 and/or MTMR15 (encoding myotubularin related proteins) alone or combined with other homozygously deleted genes as a cause for the congenital hypotonia with areflexia. The distinctive clinical findings in this patient reveal potential functions of the genes within the deleted region. Ó 2010 Wiley-Liss, Inc. Key words: microarray comparative genomic hybridization (aCGH); 15q13.3 homozygous deletion; CHRNA7; TRPM1; MTMR10; MTMR15 INTRODUCTION 15q13.3 Heterozygous microdeletions were recently recognized as genomic disorders with a spectrum of phenotypes [Sharp et al., 2008; Ben-Shachar et al., 2009; Helbig et al., 2009; Miller et al., 2009; Mulley and Dibbens, 2009; Pagnamenta et al., 2009; van Bon et al., 2009]. These heterozygous microdeletions exist in both inherited and de novo patterns. The underlying mechanism leading to these microdeletions is low copy repeat (LCR)-mediated nonallelic homologous misalignment and unequal recombination (NAHR) between two breakpoint regions (BPs), BP4 and BP5, within chromosome15q13.2q13.3 bands. The deleted sizes range from 1.5 to 2.0 Mb, harboring at least seven genes, ARHGAP11B, MTMR15, MTMR10, TRPM1, KLF13, OTUD7A, and CHRNA7. In previous reports of heterozygous deletions of these genes, only the alpha7-nicotinic receptor subunit (CHRNA7) has been dis- cussed as a candidate gene for the seizures and neuropsychiatric disturbances observed in affected individuals [Elmslie et al., 1997; Neubauer et al., 1998; Martin et al., 2007; Sharp et al., 2008; Helbig et al., 2009; Miller et al., 2009]. The genetic effects of the other genes within this deleted region remain uncertain. We report a unique patient with a 15q13.3 homozygous microdeletion whose neuro- logical features could be explained by the loss of key genes in this region. Additional supporting information may be found in the online version of this article. The authors declare no conflict of interest. *Correspondence to: Shihui Yu, Department of Pathology, Children’s Mercy Hospitals and Clinics, 2401 Gillham Rd, Kansas City, MO 64108. E-mail: syu1@cmh.edu Published online 20 April 2010 in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/ajmg.a.33374 How to Cite this Article: LePichon JB, Bittel DC, Graf WD, Yu S. 2010. A 15q13.3 homozygous microdeletion associated with a severe neurodevelopmental disorder suggests putative functions of the TRPM1, CHRNA7, and other homozygously deleted genes. Am J Med Genet Part A 152A:1300–1304. Ó 2010 Wiley-Liss, Inc. 1300