Exome Sequencing Reveals De Novo WDR45 Mutations Causing a Phenotypically Distinct, X-Linked Dominant Form of NBIA

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,...

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Published in:	American journal of human genetics 2012-12, Vol.91 (6), p.1144-1149
Main Authors:	Haack, Tobias B., Hogarth, Penelope, Kruer, Michael C., Gregory, Allison, Wieland, Thomas, Schwarzmayr, Thomas, Graf, Elisabeth, Sanford, Lynn, Meyer, Esther, Kara, Eleanna, Cuno, Stephan M., Harik, Sami I., Dandu, Vasuki H., Nardocci, Nardo, Zorzi, Giovanna, Dunaway, Todd, Tarnopolsky, Mark, Skinner, Steven, Frucht, Steven, Hanspal, Era, Schrander-Stumpel, Connie, Héron, Delphine, Mignot, Cyril, Garavaglia, Barbara, Bhatia, Kailash, Hardy, John, Strom, Tim M., Boddaert, Nathalie, Houlden, Henry H., Kurian, Manju A., Meitinger, Thomas, Prokisch, Holger, Hayflick, Susan J.
Format:	Article
Language:	eng
Subjects:	Age Alleles Amino Acid Sequence Autophagy Basal ganglia Base Sequence Biological and medical sciences Brain Brain - metabolism Brain - pathology Carrier Proteins - genetics Central nervous system diseases Dementia disorders Dystonia Exome Female Fundamental and applied biological sciences. Psychology Gene Order Genes, X-Linked Genetic disorders Genetics of eukaryotes. Biological and molecular evolution Genotype & phenotype Globus pallidus High-Throughput Nucleotide Sequencing Humans Iron Iron Overload - diagnosis Iron Overload - genetics Magnetic Resonance Imaging Male Medical genetics Medical sciences Molecular and cellular biology Molecular Sequence Data Mosaicism Movement disorders Mutation Neurodegeneration NMR Nuclear magnetic resonance Phagocytosis Phenotype scaffolds Signal transduction Substantia nigra X chromosome X-chromosome inactivation
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Summary:	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.
ISSN:	0002-9297 1537-6605