title: Identification of mutation in NPC2 by exome sequencing results in diagnosis of Niemann-Pick disease type C.
abstract: We report identification of a homozygous mutation in NPC2 in two Iranian siblings with a neurologic dysfunction whose disease had not been diagnosed prior to our genetic analysis. The mutation was identified by exome sequencing. The finding resulted in diagnosis of Niemann-Pick disease type C (NPC) in the siblings, and initiation of treatment with Miglustat. The clinical features of the patients are presented. It has been suggested that NPC is under diagnosed, particularly when presentations are not very severe, as was the situation in the cases studied here. NPC is a fatal autosomal recessive disorder clinically characterized by hepatosplenomegaly and progressive neurological deterioration. At the cellular level, it causes aberrant cholesterol trafficking and accumulation of unesterified cholesterol in lysosomes. Mutations in NPC1 and NPC2 are cause of disease in respectively, 95% and 5% of NPC patients. The p.Pro120Ser causing mutation in NPC2 observed in the Iranian patients was earlier observed in the only other NPC2 patient reported from the Middle East. The study demonstrates that in addition to greatly facilitating gene discovery, exome sequencing has notable potentials for diagnosis, particularly for diagnosis of atypical cases.
authors.affiliation: School of Biology, College of Science, University of Tehran, Tehran, Iran.
authors.forename: Afagh
authors.initials: A
authors.lastname: Alavi
authors.forename: Shahriar
authors.initials: S
authors.lastname: Nafissi
authors.forename: Hosein
authors.initials: H
authors.lastname: Shamshiri
authors.forename: Maryam Malakooti
authors.initials: MM
authors.lastname: Nejad
authors.forename: Elahe
authors.initials: E
authors.lastname: Elahi
mesh_terms: D000293:Adolescent; D000328:Adult; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D059472:Exome / Q000235:genetics; D005260:Female; D005820:Genetic Testing; D005838:Genotype; D006023:Glycoproteins / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007492:Iran; D008297:Male; D009154:Mutation; D052556:Niemann-Pick Disease, Type C / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D033921:Vesicular Transport Proteins
chemical_list: D002352:Carrier Proteins; D006023:Glycoproteins; C104585:NPC2 protein, human; D033921:Vesicular Transport Proteins
keywords: ALS; C9orf72; DTR; Exome sequencing; HGMD; LDL; MRI; NPC; NPC1; NPC1 gene; NPC2; NPC2 gene; Niemann–Pick C; Niemann–Pick type C; PCR-RFLP; SMPD1; SOD1; Superoxide desmutase 1 gene; The Human Gene Mutation Database; amyotrophic lateral sclerosis; chromosome 9 open reading frame 72 gene; deep tendon reflex; low density lipoprotein; magnetic resonance imaging; p.Pro120Ser; polymerase chain reaction-restriction fragment length polymorphism; sphingomyelin phosphodiesterase 1 gene