title: Apparent genotype-phenotype correlation in childhood, adolescent, and adult Chediak-Higashi syndrome.
abstract: Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disorder characterized by severe immunologic defects, reduced pigmentation, bleeding tendency, and progressive neurological dysfunction. Most patients present in early childhood and die unless treated by bone marrow transplantation. About 10-15% of patients exhibit a much milder clinical phenotype and survive to adulthood, but develop progressive and often fatal neurological dysfunction. Very rare patients exhibit an intermediate adolescent CHS phenotype, presenting with severe infections in early childhood, but a milder course by adolescence, with no accelerated phase. Here, we describe the organization and genomic DNA sequence of the CHS1 gene and mutation analysis of 21 unrelated patients with the childhood, adolescent, and adult forms of CHS. In patients with severe childhood CHS, we found only functionally null mutant CHS1 alleles, whereas in patients with the adolescent and adult forms of CHS we also found missense mutant alleles that likely encode CHS1 polypeptides with partial function. Together, these results suggest an allelic genotype-phenotype relationship among the various clinical forms of CHS.
authors.affiliation: Human Medical Genetics Program, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Karim
authors.forename: Koji
authors.initials: K
authors.lastname: Suzuki
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Fukai
authors.forename: Jangsuk
authors.initials: J
authors.lastname: Oh
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Nagle
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Moore
authors.forename: Ernest
authors.initials: E
authors.lastname: Barbosa
authors.forename: Tzipora
authors.initials: T
authors.lastname: Falik-Borenstein
authors.forename: Alexandra
authors.initials: A
authors.lastname: Filipovich
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ishida
authors.forename: Sirpa
authors.initials: S
authors.lastname: Kivrikko
authors.forename: Christoph
authors.initials: C
authors.lastname: Klein
authors.forename: Friedmar
authors.initials: F
authors.lastname: Kreuz
authors.forename: Alex
authors.initials: A
authors.lastname: Levin
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Miyajima
authors.forename: Jose R
authors.initials: JR
authors.lastname: Regueiro
authors.forename: Carolyn
authors.initials: C
authors.lastname: Russo
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Uyama
authors.forename: Outi
authors.initials: O
authors.lastname: Vierimaa
authors.forename: Richard A
authors.initials: RA
authors.lastname: Spritz
mesh_terms: D000293:Adolescent; D000328:Adult; D002609:Chediak-Higashi Syndrome / Q000235:genetics* / Q000503:physiopathology; D002675:Child, Preschool; D022202:Chromosomes, Artificial, Bacterial; D027042:Chromosomes, Artificial, P1 Bacteriophage; D018389:Codon, Nonsense; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D019143:Evolution, Molecular; D005091:Exons; D016368:Frameshift Mutation; D005656:Fungal Proteins / Q000235:genetics*; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D007438:Introns; D020125:Mutation, Missense; D010641:Phenotype; D017422:Sequence Analysis, DNA
chemical_list: C430064:CSH1 protein, Candida albicans; D018389:Codon, Nonsense; D005656:Fungal Proteins