Genome sequencing in a case of Niemann–Pick type C

• DOI: 10.1101/mcs.a001222
• Publication Date: 2016-09-16T22:39:36Z
• Authors: Max Dougherty; John Lazar; Jason C. Klein; Karina Diaz; Theodore Gobillot; Eli Grunblatt; Nicholas Hasle; Daniel Lawrence; Megan Maurano; Maria Nelson; Gregory Olson; Sanjay Srivatsan; Jay Shendure; C. Dirk Keene; Thomas Bird; Marshall S. Horwitz; Desiree A. Marshall
• Keywords: NPC1; Niemann–Pick disease; Genome-wide Association Study

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 in NPC1 (∼95%) or NPC2 (∼5%). Our patient was diagnosed at age 33 when he presented with 10-yr history difficulties judgment, concentration, speech, and coordination. A transient neonatal jaundice splenomegaly bone marrow biopsy suggesting pointed to NPC; biochemical (“variant” level cholesterol esterification) ultrastructural studies adulthood confirmed the diagnosis. Genetic testing revealed two different missense gene—V950M N1156S. Symptoms progressed over >20 yr severe ataxia spasticity, dementia, dysphagia aspiration leading death. Brain autopsy mild atrophy cerebrum cerebellum. Microscopic examination showed diffuse gray matter deposition balloon neurons, white loss, extensive cerebellar Purkinje cell loss numerous “empty baskets,” neurofibrillary tangles predominantly hippocampal formation transentorhinal cortex. We performed whole-genome sequencing examine whether harbored variants outside locus that could have contributed his late-onset phenotype. focused analysis on genetic modifiers pathways related metabolism, longevity, neurodegenerative disease. identified no coding any examined nor enriched for genome-wide association study (GWAS) single-nucleotide polymorphisms (SNPs) associated longevity altered metabolism. In light these findings, this case provides support V950M variant being sufficient adult-onset NPC