title: TCIRG1-associated congenital neutropenia.
abstract: Severe congenital neutropenia (SCN) is a rare hematopoietic disorder, with estimated incidence of 1 in 200,000 individuals of European descent, many cases of which are inherited in an autosomal dominant pattern. Despite the fact that several causal genes have been identified, the genetic basis for >30% of cases remains unknown. We report a five-generation family segregating a novel single nucleotide variant (SNV) in TCIRG1. There is perfect cosegregation of the SNV with congenital neutropenia in this family; all 11 affected, but none of the unaffected, individuals carry this novel SNV. Western blot analysis show reduced levels of TCIRG1 protein in affected individuals, compared to healthy controls. Two unrelated patients with SCN, identified by independent investigators, are heterozygous for different, rare, highly conserved, coding variants in TCIRG1.
authors.affiliation: Department of Medicine, Divisions of GIM, University of Washington, Seattle, Washington.
authors.forename: Vahagn
authors.initials: V
authors.lastname: Makaryan
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Rosenthal
authors.forename: Audrey Anna
authors.initials: AA
authors.lastname: Bolyard
authors.forename: Merideth L
authors.initials: ML
authors.lastname: Kelley
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Below
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bamshad
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Bofferding
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Smith
authors.forename: Kati
authors.initials: K
authors.lastname: Buckingham
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Boxer
authors.forename: Julia
authors.initials: J
authors.lastname: Skokowa
authors.forename: Karl
authors.initials: K
authors.lastname: Welte
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.forename: Gail P
authors.initials: GP
authors.lastname: Jarvik
authors.forename: David C
authors.initials: DC
authors.lastname: Dale
mesh_terms: D000080984:Congenital Bone Marrow Failure Syndromes; D004252:DNA Mutational Analysis; D006579:Heterozygote; D006801:Humans; D009154:Mutation; D009503:Neutropenia / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D010375:Pedigree; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics* / Q000378:metabolism
chemical_list: C472421:TCIRG1 protein, human; D025262:Vacuolar Proton-Translocating ATPases
keywords: SCN; TCIRG1; V-ATPase; congenital neutropenia
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