Molecular Genetics and Metabolism 85 (2005) 125–132 www.elsevier.com/locate/ymgme 1096-7192/$ - see front matter. Published by Elsevier Inc. doi:10.1016/j.ymgme.2005.02.011 Two novel CHS1 (LYST) mutations: Clinical correlations in an infant with Chediak–Higashi syndrome WaWka Zarzour a,b,1 , Robert Kleta a,c , Haydar Frangoul d , Pim Suwannarat a , Anna Jeong a , Su Young Kim e , Alan S. Wayne e , Meral Gunay-Aygun a,c , James White f , Alexandra H. Filipovich g , William A. Gahl a,c,¤ a Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA b Department of Biochemistry, Faculty of Pharmacy, Damascus University, Syria c OYce of Rare Diseases, Intramural Program, OYce of the Director, National Institutes of Health, Bethesda, MD 20892, USA d Pediatric Hematology/Oncology, Vanderbilt Children’s Hospital, Nashville, TN 37232, USA e Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA f Department of Laboratory Medicine, University of Minnesota, Minneapolis, MN, USA g Division of Hematology/Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229-3039, USA Received 17 January 2005; received in revised form 14 February 2005; accepted 14 February 2005 Available online 25 March 2005 Abstract Chediak–Higashi syndrome (CHS) is a rare autosomal recessive disease characterized by variable degrees of oculocutaneous albi- nism, recurrent infections, and a mild bleeding tendency, with late neurologic dysfunction. Most patients also undergo an accelerated phase of lymphohistiocytosis and die at an early age unless they receive an allogeneic hematopoietic stem cell transplant (SCT). Mutations in the CHS1 (LYST) gene result in CHS. Here, we describe an adopted infant who is compound heterozygous for two novel CHS1 gene mutations, both of which are predicted to result in truncated proteins. The two mutations are a nonsense mutation (c.1540 C > T, CGA > TGA, R514X) in exon 5 and a one base pair deletion (del c.9893T, F3298fsX3304) in exon 43, coding for part of the CHS1 protein’s BEACH domain. These two newly described mutations are expected to give rise to a severe phenotype and, indeed, the patient had absolutely no cytotoxicity by natural killer cells or cytotoxic lymphocytes prior to his allogeneic SCT. Published by Elsevier Inc. Keywords: Chediak–Higashi syndrome; CHS1; LYST; BEACH; Mutation analysis Introduction Chediak–Higashi syndrome (CHS; MIM #214500) is a rare autosomal recessive disease whose clinical and hematological Wndings were described Wve decades ago by Chediak [1] and Higashi [2]. Characteristic features include decreased pigmentation of skin, hair, and eyes, large eosinophilic, peroxidase-positive inclusion bodies in circulating granulocytes and other cell types, neutropenia, and increased susceptibility to infection [3–5]. Other Wnd- ings are platelet dysfunction with normal microtubules but absent or rare dense bodies [6–8], defective granulo- cyte chemotaxis [9], abnormal natural killer (NK) cell function [10], and defective structure or function of mela- nosomes in melanocytes [11]. A lymphoproliferative his- tiocytosis called the accelerated phase [12,13] often leads to death within the Wrst decade [3,5], and a peripheral neuropathy strikes in the second or third decade [14–16]. * Corresponding author. Fax +1 301 402 2740. E-mail address: bgahl@helix.nih.gov (W.A. Gahl). 1 Fulbright Senior Scholar, 2004.