title: Whole Genome Sequencing Identifies Novel Compound Heterozygous Lysosomal Trafficking Regulator Gene Mutations Associated with Autosomal Recessive Chediak-Higashi Syndrome.
abstract: Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disease characterized by varying degrees of oculocutaneous albinism, recurrent infections, and a mild bleeding tendency, with late neurologic dysfunction. This syndrome is molecularly characterized by pathognomonic mutations in the LYST (lysosomal trafficking regulator). Using whole genome sequencing (WGS) we attempted to identify novel mutations of CHS based on a family of CHS with atypical symptoms. The two patients demonstrated a phenotypic constellation including partial oculocutaneous albinism, frequency upper respiratory infection or a marginal intelligence, without bleeding tendency and severe immunodeficiency. WGS revealed two compound LYST mutations including a maternally inherited chr1:235969126G > A (rs80338652) and a novel paternally inherited chr1: 235915327A > AT, associated with autosomal recessive CHS. These two variants fall in the coding regions of LYST, resulting in premature truncation of LYST due to R1104X/N2535KfsX2 induced incomplete translation. Notably, the heterozygous carriers (i.e. parents) were unaffected. Our finding also reveals decreased plasma serotonin levels in patients with CHS compared with unaffected individuals for the first time. The present study contributes to improved understanding of the causes of this disease and provides new ideas for possible treatments.
authors.affiliation: Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, MOE Key Laboratory of Major Diseases in Children, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing, China.|Biobank for Clinical Data and Samples in Pediatric, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing, China.
authors.forename: Yaqiong
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Center for Bioinformatics and Computational Biology, and the Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Dermatology, Beijing Children's Hospital, Capital Medical University, Beijing, China.
authors.forename: Senfen
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Beijing Children's Hospital, Capital Medical University, Beijing, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of Dermatology, Beijing Children's Hospital, Capital Medical University, Beijing, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Biobank for Clinical Data and Samples in Pediatric, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing, China.
authors.forename: Enyu
authors.initials: E
authors.lastname: Hong
authors.affiliation: Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, MOE Key Laboratory of Major Diseases in Children, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing, China.
authors.forename: Yongbo
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, MOE Key Laboratory of Major Diseases in Children, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing, China.|Biobank for Clinical Data and Samples in Pediatric, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing, China.|Department of Otolaryngology, Head and Neck Surgery, Beijing Children's Hospital, Capital Medical University, Beijing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Ni
authors.affiliation: Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, MOE Key Laboratory of Major Diseases in Children, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing, China.|Biobank for Clinical Data and Samples in Pediatric, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing, China.
authors.forename: Yongli
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Center for Bioinformatics and Computational Biology, and the Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Tieliu
authors.initials: T
authors.lastname: Shi
authors.affiliation: Department of Dermatology, Beijing Children's Hospital, Capital Medical University, Beijing, China.
authors.forename: Zigang
authors.initials: Z
authors.lastname: Xu
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D001483:Base Sequence; D002609:Chediak-Higashi Syndrome / Q000097:blood / Q000235:genetics*; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D015203:Reproducibility of Results; D012701:Serotonin / Q000097:blood; D033921:Vesicular Transport Proteins / Q000737:chemistry / Q000235:genetics*; D000073336:Whole Genome Sequencing
chemical_list: C102161:LYST protein, human; D033921:Vesicular Transport Proteins; D012701:Serotonin