Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct, X-linked dominant form of NBIA

Tobias B Haack, Penelope Hogarth, Michael C Kruer, Allison Gregory, Thomas Wieland, Thomas Schwarzmayr, Elisabeth Graf, Lynn Sanford, Esther Meyer, Eleanna Kara, Stephan M Cuno, Sami I Harik, Vasuki H Dandu, Nardo Nardocci, Giovanna Zorzi, Todd Dunaway, Mark Tarnopolsky, Steven Skinner, Steven Frucht, Era Hanspal, Connie Schrander-Stumpel, Delphine Héron, Cyril Mignot, Barbara Garavaglia, Kailash Bhatia, John Hardy, Tim M Strom, Nathalie Boddaert, Henry H Houlden, Manju A Kurian, Thomas Meitinger, Holger Prokisch, Susan J Hayflick
American Journal of Human Genetics 2012 December 7, 91 (6): 1144-9
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.

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