title: Chediak-Higashi syndrome with early developmental delay resulting from paternal heterodisomy of chromosome 1.
abstract: Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disease characterized by variable oculocutaneous albinism, immunodeficiency, mild bleeding diathesis, and an accelerated lymphoproliferative state. Abnormal lysosome-related organelle membrane function leads to the accumulation of large intracellular vesicles in several cell types, including granulocytes, melanocytes, and platelets. This report describes a severe case of CHS resulting from paternal heterodisomy of chromosome 1, causing homozygosity for the most distal nonsense mutation (p.E3668X, exon 50) reported to date in the LYST/CHS1 gene. The mutation is located in the WD40 region of the CHS1 protein. The patient's fibroblasts expressed no detectable CHS1. Besides manifesting the classical CHS findings, the patient exhibited hypotonia and global developmental delays, raising concerns about other effects of heterodisomy. An interstitial 747 kb duplication on 6q14.2-6q14.3 was identified in the propositus and paternal samples by comparative genomic hybridization. SNP genotyping revealed no additional whole chromosome or segmental isodisomic regions or other dosage variations near the crossover breakpoints on chromosome 1. Unmasking of a separate autosomal recessive cause of developmental delay, or an additive effect of the paternal heterodisomy, could underlie the severity of the phenotype in this patient.
authors.affiliation: Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA. manolii@mail.nih.gov
authors.forename: Irini
authors.initials: I
authors.lastname: Manoli
authors.forename: Gretchen
authors.initials: G
authors.lastname: Golas
authors.forename: Wendy
authors.initials: W
authors.lastname: Westbroek
authors.forename: Thierry
authors.initials: T
authors.lastname: Vilboux
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Markello
authors.forename: Wendy
authors.initials: W
authors.lastname: Introne
authors.forename: Dawn
authors.initials: D
authors.lastname: Maynard
authors.forename: Ben
authors.initials: B
authors.lastname: Pederson
authors.forename: Ekaterini
authors.initials: E
authors.lastname: Tsilou
authors.forename: Michael B
authors.initials: MB
authors.lastname: Jordan
authors.forename: P Suzanne
authors.initials: PS
authors.lastname: Hart
authors.forename: James G
authors.initials: JG
authors.lastname: White
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.forename: Marjan
authors.initials: M
authors.lastname: Huizing
mesh_terms: D000782:Aneuploidy; D002609:Chediak-Higashi Syndrome / Q000235:genetics* / Q000473:pathology; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D018389:Codon, Nonsense; D005091:Exons / Q000235:genetics; D005347:Fibroblasts / Q000473:pathology; D006801:Humans; D007223:Infant; D008247:Lysosomes / Q000473:pathology; D012160:Retina / Q000473:pathology; D017422:Sequence Analysis, DNA
chemical_list: D018389:Codon, Nonsense