title: Phenotype diversity in type 1 Gaucher disease: discovering the genetic basis of Gaucher disease/hematologic malignancy phenotype by individual genome analysis.
abstract: Gaucher disease (GD), an inherited macrophage glycosphingolipidosis, manifests with an extraordinary variety of phenotypes that show imperfect correlation with mutations in the GBA gene. In addition to the classic manifestations, patients suffer from increased susceptibility to hematologic and nonhematologic malignancies. The mechanism(s) underlying malignancy in GD is not known, but is postulated to be secondary to macrophage dysfunction and immune dysregulation arising from lysosomal accumulation of glucocerebroside. However, there is weak correlation between GD/cancer phenotype and the systemic burden of glucocerebroside-laden macrophages. Therefore, we hypothesized that genetic modifier(s) may underlie the GD/cancer phenotype. In the present study, the genetic basis of GD/T-cell acute lymphoblastic lymphoma in 2 affected siblings was deciphered through genomic analysis. GBA gene sequencing revealed homozygosity for a novel mutation, D137N. Whole-exome capture and massively parallel sequencing combined with homozygosity mapping identified a homozygous novel mutation in the MSH6 gene that leads to constitutional mismatch repair deficiency syndrome and increased cancer risk. Enzyme studies demonstrated that the D137N mutation in GBA is a pathogenic mutation, and immunohistochemistry confirmed the absence of the MSH6 protein. Therefore, precise phenotype annotation followed by individual genome analysis has the potential to identify genetic modifiers of GD, facilitate personalized management, and provide novel insights into disease pathophysiology.
authors.affiliation: Section of Pediatric Hematology-Oncology, Department of Pediatrics, Yale School of Medicine, 333 Cedar St., New Haven, CT 06520, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Lo
authors.forename: Murim
authors.initials: M
authors.lastname: Choi
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Dhanpat
authors.initials: D
authors.lastname: Jain
authors.forename: Rolf G
authors.initials: RG
authors.lastname: Boot
authors.forename: Wouter W
authors.initials: WW
authors.lastname: Kallemeijn
authors.forename: Johannes M F G
authors.initials: JM
authors.lastname: Aerts
authors.forename: Farzana
authors.initials: F
authors.lastname: Pashankar
authors.forename: Gary M
authors.initials: GM
authors.lastname: Kupfer
authors.forename: Shrikant
authors.initials: S
authors.lastname: Mane
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
authors.forename: Pramod K
authors.initials: PK
authors.lastname: Mistry
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D005776:Gaucher Disease / Q000150:complications / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D015894:Genome, Human / Q000235:genetics; D019337:Hematologic Neoplasms / Q000150:complications / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007206:Individuality; D008297:Male; D010375:Pedigree; D010641:Phenotype; D017422:Sequence Analysis, DNA; D035781:Siblings; D001617:beta-Glucosidase / Q000032:analysis / Q000235:genetics
chemical_list: D001617:beta-Glucosidase