title: Genome sequencing in a case of Niemann-Pick type C.
abstract: Adult-onset Niemann-Pick disease type C (NPC) is an infrequent presentation of a rare neurovisceral lysosomal lipid storage disorder caused by autosomal recessive mutations inNPC1(∼95%) orNPC2(∼5%). Our patient was diagnosed at age 33 when he presented with a 10-yr history of difficulties in judgment, concentration, speech, and coordination. A history of transient neonatal jaundice and splenomegaly with bone marrow biopsy suggesting a lipid storage disorder pointed to NPC; biochemical ("variant" level cholesterol esterification) and ultrastructural studies in adulthood confirmed the diagnosis. Genetic testing revealed two different missense mutations in theNPC1gene-V950M and N1156S. Symptoms progressed over >20 yr to severe ataxia and spasticity, dementia, and dysphagia with aspiration leading to death. Brain autopsy revealed mild atrophy of the cerebrum and cerebellum. Microscopic examination showed diffuse gray matter deposition of balloon neurons, mild white matter loss, extensive cerebellar Purkinje cell loss with numerous "empty baskets," and neurofibrillary tangles predominantly in the hippocampal formation and transentorhinal cortex. We performed whole-genome sequencing to examine whether the patient harbored variants outside of theNPC1locus that could have contributed to his late-onset phenotype. We focused analysis on genetic modifiers in pathways related to lipid metabolism, longevity, and neurodegenerative disease. We identified no rare coding variants in any of the pathways examined nor was the patient enriched for genome-wide association study (GWAS) single-nucleotide polymorphisms (SNPs) associated with longevity or altered lipid metabolism. In light of these findings, this case provides support for the V950M variant being sufficient for adult-onset NPC disease.
authors.affiliation: University of Washington School of Medicine, Seattle, Washington 98195, USA;; Medical Scientist Training Program (MSTP), University of Washington, Seattle, Washington 98195, USA;; Department of Genome Sciences, University of Washington, Seattle, Washington 98105, USA.
authors.forename: Max
authors.initials: M
authors.lastname: Dougherty
authors.affiliation: University of Washington School of Medicine, Seattle, Washington 98195, USA;; Medical Scientist Training Program (MSTP), University of Washington, Seattle, Washington 98195, USA;; Department of Genome Sciences, University of Washington, Seattle, Washington 98105, USA.
authors.forename: John
authors.initials: J
authors.lastname: Lazar
authors.affiliation: University of Washington School of Medicine, Seattle, Washington 98195, USA;; Medical Scientist Training Program (MSTP), University of Washington, Seattle, Washington 98195, USA;; Department of Genome Sciences, University of Washington, Seattle, Washington 98105, USA.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Klein
authors.affiliation: University of Washington School of Medicine, Seattle, Washington 98195, USA;; Medical Scientist Training Program (MSTP), University of Washington, Seattle, Washington 98195, USA.
authors.forename: Karina
authors.initials: K
authors.lastname: Diaz
authors.affiliation: University of Washington School of Medicine, Seattle, Washington 98195, USA;; Medical Scientist Training Program (MSTP), University of Washington, Seattle, Washington 98195, USA.
authors.forename: Theodore
authors.initials: T
authors.lastname: Gobillot
authors.affiliation: University of Washington School of Medicine, Seattle, Washington 98195, USA;; Medical Scientist Training Program (MSTP), University of Washington, Seattle, Washington 98195, USA.
authors.forename: Eli
authors.initials: E
authors.lastname: Grunblatt
authors.affiliation: University of Washington School of Medicine, Seattle, Washington 98195, USA;; Medical Scientist Training Program (MSTP), University of Washington, Seattle, Washington 98195, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Hasle
authors.affiliation: University of Washington School of Medicine, Seattle, Washington 98195, USA;; Medical Scientist Training Program (MSTP), University of Washington, Seattle, Washington 98195, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lawrence
authors.affiliation: University of Washington School of Medicine, Seattle, Washington 98195, USA;; Medical Scientist Training Program (MSTP), University of Washington, Seattle, Washington 98195, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Maurano
authors.affiliation: University of Washington School of Medicine, Seattle, Washington 98195, USA;; Medical Scientist Training Program (MSTP), University of Washington, Seattle, Washington 98195, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Nelson
authors.affiliation: University of Washington School of Medicine, Seattle, Washington 98195, USA;; Medical Scientist Training Program (MSTP), University of Washington, Seattle, Washington 98195, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Olson
authors.affiliation: University of Washington School of Medicine, Seattle, Washington 98195, USA;; Medical Scientist Training Program (MSTP), University of Washington, Seattle, Washington 98195, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Srivatsan
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98105, USA;; Howard Hughes Medical Institute, Seattle, Washington 98195, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington 98195, USA.
authors.forename: C Dirk
authors.initials: CD
authors.lastname: Keene
authors.affiliation: Department of Neurology, University of Washington, Seattle, Washington 98105, USA;; Department of Medicine, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bird
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Marshall S
authors.initials: MS
authors.lastname: Horwitz
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Desiree A
authors.initials: DA
authors.lastname: Marshall
mesh_terms: D001483:Base Sequence; D001921:Brain / Q000166:cytology / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D003704:Dementia / Q000235:genetics; D005820:Genetic Testing; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D020125:Mutation, Missense; D019636:Neurodegenerative Diseases / Q000235:genetics; D016874:Neurofibrillary Tangles / Q000378:metabolism; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000235:genetics*; D009542:Niemann-Pick Diseases / Q000235:genetics; D000073336:Whole Genome Sequencing / Q000379:methods
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein
keywords: atrophy/degeneration affecting the cerebrum; central nervous system degeneration; falls; hepatosplenomegaly; neurodegeneration; neuronal loss in central nervous system; progressive encephalopathy; progressive forgetfulness; progressive language deterioration; progressive psychomotor deterioration; slowed slurred speech; social and occupational deterioration