BRIEF COMMUNICATION Chédiak–Higashi syndrome presenting as a hereditary spastic paraplegia Kishin Koh 1 , Mai Tsuchiya 1 , Hiroyuki Ishiura 2 , Haruo Shimazaki 3,4 , Takeshi Nakamura 5 , Hideo Hara 6 , Kohei Suzuyama 6 , Makio Takahashi 7 , Shoji Tsuji 8,9 , Yoshihisa Takiyama 1 ✉ Japan Spastic Paraplegia Research Consortium © The Author(s), under exclusive licence to The Japan Society of Human Genetics 2021 Hereditary spastic paraplegias (HSPs) comprise a group of neurodegenerative disorders characterized by weakness and leg spasticity. LYST is responsible for Chédiak–Higashi syndrome (CHS), which exhibits partial oculocutaneous albinism, primary immunodeficiency, and bleeding tendency in childhood. Although neurological symptoms of CHS also appear in adulthood, a phenotype of spastic paraplegia has rarely been reported in CHS. In this study, we investigated LYST mutations in 387 HSP patients through the Japan Spastic Paraplegia Research Consortium to clarify the frequency of LYST mutations in HSP, finding six adult patients with LYST mutations in four HSP families. They exhibited intellectual disability, cerebellar ataxia, neuropathy, and pyramidal signs. Meanwhile, only 15 patients with CHS in childhood have been revealed in a decade by a nationwide survey in Japan. Thus, LYST mutations might indicate a HSP phenotype in a considerable number of adult patients with CHS. Journal of Human Genetics; https://doi.org/10.1038/s10038-021-00977-z INTRODUCTION Hereditary spastic paraplegias (HSPs) comprise a group of neurodegenerative disorders characterized by weakness and leg spasticity [1]. To date, many causative genes or loci of HSPs have been reported (SPG1-SPG83). Furthermore, other inherited dis- eases sometimes involve spastic paraplegia as one of the symptoms. We reported complicated HSP with LYST mutations in 2014 [2]. LYST is responsible for the regulation of lysosomal trafficking and the synthesis, fusion, and transport of cytoplasmic granules, and causes Chédiak–Higashi syndrome (CHS; OMIM #214500) with autosomal recessive inheritance. CHS involves partial oculocutaneous albinism, primary immunodeficiency, and bleeding tendency in childhood [3]. Most affected individuals develop an accelerated phase or hemophagocytic lymphohistio- cytosis, a life-threatening and hyperinflammatory condition. Known neurological symptoms of CHS are cognitive impairment, peripheral neuropathy, ataxia, and parkinsonism [3]. After our first report [2], we encountered the second HSP patient with a LYST mutation [4], concluding that HSP might include LYST mutations. Thus, we attempted to determine the frequency of LYST mutations in HSP patients through the Japan Spastic Paraplegia Research Consortium (JASPAC) [5]. MATERIALS AND METHODS This study was approved by our institutional review board, and written informed consent for participation and publication was obtained from all the participants. We conducted whole-exome sequence analysis to screen for LYST variations in 387 HSP patients who were referred to the JASPAC. We excluded common LYST variants using gnomAD [6], dbSNP [7], the Human Genetic Variation Database (HGVD) [8], and in-house variant data for 1261 control subjects. Functional prediction was conducted by in silico analysis including PolyPhen2 [9], SIFT [10], and CADD [11]. We collected genomic DNSs from family members of patients with LYST mutations. We applied the Sanger sequence to patients and their family members for a co- segregation study. Clinical information was collected from their medical records. RESULTS We found six patients with LYST mutations in four families through the JASPAC (Fig. 1). The HSP families have c.4189T>G/c.4189T>G, p.Phe1397Val/p.Phe1397Val [2], c.172C>G/c.172C>G, p.Leu58Val/ p.Leu58Val [4], c.4157delA/c.9476A>G, p.Asp1386Valfs*4/p. Asp3159Gly, and c.8221C>T/c.10374+1G>T, p.Arg2741*/splice site mutation, respectively. All detected mutations were novel ones, and did not appear in gnomAD [6], dbSNP [7], HGVD [8], or the in- house variant data for 1261 control subjects. Each mutation was consistent with autosomal recessive inheritance in Families A, B, and C (Fig. 1). We could not determine whether or not there was a compound heterozygous mutation in Family D. Functional prediction of missense mutations (c.4189T>G, c.172C>G, and c.9476A>G) was performed with PolyPhen2, SIFT, and CADD. Polyphen2 predicted that these three missense mutations were Received: 27 June 2021 Revised: 10 August 2021 Accepted: 25 August 2021 1 Department of Neurology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, Japan. 2 Department of Neurology, The University of Tokyo, Tokyo, Japan. 3 Faculty of Health & Medical Care, Saitama Medical University, Saitama, Japan. 4 Department of Neurology, Saitama Medical University Hospital, Saitama, Japan. 5 Department of Neurology, Kyoto Takeda Hospital, Kyoto, Japan. 6 Division of Neurology, Department of Internal Medicine, Saga University Faculty of Medicine, Saga, Japan. 7 Department of Neurology, Kitano Hospital Medical Research Institute, The Tazuke-Kofukai, Osaka, Japan. 8 Department of Molecular Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. 9 Institute of Medical Genomics, International University of Health and Welfare, Chiba, Japan. ✉ email: ytakiyama@yamanashi.ac.jp www.nature.com/jhg