title: Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct, X-linked dominant form of NBIA.
abstract: Neurodegeneration with brain iron accumulation (NBIA) is a group of genetic disorders characterized by abnormal iron deposition in the basal ganglia. We report that de novo mutations in WDR45, a gene located at Xp11.23 and encoding a beta-propeller scaffold protein with a putative role in autophagy, cause a distinctive NBIA phenotype. The clinical features include early-onset global developmental delay and further neurological deterioration (parkinsonism, dystonia, and dementia developing by early adulthood). Brain MRI revealed evidence of iron deposition in the substantia nigra and globus pallidus. Males and females are phenotypically similar, an observation that might be explained by somatic mosaicism in surviving males and germline or somatic mutations in females, as well as skewing of X chromosome inactivation. This clinically recognizable disorder is among the more common forms of NBIA, and we suggest that it be named accordingly as beta-propeller protein-associated neurodegeneration.
authors.affiliation: Institute of Human Genetics, Technische Universität München, 85748 Munich, Germany.
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Haack
authors.forename: Penelope
authors.initials: P
authors.lastname: Hogarth
authors.forename: Michael C
authors.initials: MC
authors.lastname: Kruer
authors.forename: Allison
authors.initials: A
authors.lastname: Gregory
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
authors.forename: Thomas
authors.initials: T
authors.lastname: Schwarzmayr
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Graf
authors.forename: Lynn
authors.initials: L
authors.lastname: Sanford
authors.forename: Esther
authors.initials: E
authors.lastname: Meyer
authors.forename: Eleanna
authors.initials: E
authors.lastname: Kara
authors.forename: Stephan M
authors.initials: SM
authors.lastname: Cuno
authors.forename: Sami I
authors.initials: SI
authors.lastname: Harik
authors.forename: Vasuki H
authors.initials: VH
authors.lastname: Dandu
authors.forename: Nardo
authors.initials: N
authors.lastname: Nardocci
authors.forename: Giovanna
authors.initials: G
authors.lastname: Zorzi
authors.forename: Todd
authors.initials: T
authors.lastname: Dunaway
authors.forename: Mark
authors.initials: M
authors.lastname: Tarnopolsky
authors.forename: Steven
authors.initials: S
authors.lastname: Skinner
authors.forename: Steven
authors.initials: S
authors.lastname: Frucht
authors.forename: Era
authors.initials: E
authors.lastname: Hanspal
authors.forename: Connie
authors.initials: C
authors.lastname: Schrander-Stumpel
authors.forename: Delphine
authors.initials: D
authors.lastname: Héron
authors.forename: Cyril
authors.initials: C
authors.lastname: Mignot
authors.forename: Barbara
authors.initials: B
authors.lastname: Garavaglia
authors.forename: Kailash
authors.initials: K
authors.lastname: Bhatia
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boddaert
authors.forename: Henry H
authors.initials: HH
authors.lastname: Houlden
authors.forename: Manju A
authors.initials: MA
authors.lastname: Kurian
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Hayflick
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D001483:Base Sequence; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D059472:Exome; D005260:Female; D023061:Gene Order; D050172:Genes, X-Linked; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D019190:Iron Overload / Q000175:diagnosis / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype
chemical_list: D002352:Carrier Proteins; C578284:WDR45 protein, human