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

• Published in: American journal of human genetics Vol. 91; no. 6; pp. 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: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 07.12.2012; Cell Press; Elsevier
• 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; Sex linked character; Nucleotide sequence; Genetics; Dominant character; X-Chromosome; Mutation; Sequencing; De novo; Genetic disease
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2012.10.019

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.