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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.

SUBMITTER: Haack TB 

PROVIDER: S-EPMC3516593 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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

Haack Tobias B TB   Hogarth Penelope P   Kruer Michael C MC   Gregory Allison A   Wieland Thomas T   Schwarzmayr Thomas T   Graf Elisabeth E   Sanford Lynn L   Meyer Esther E   Kara Eleanna E   Cuno Stephan M SM   Harik Sami I SI   Dandu Vasuki H VH   Nardocci Nardo N   Zorzi Giovanna G   Dunaway Todd T   Tarnopolsky Mark M   Skinner Steven S   Frucht Steven S   Hanspal Era E   Schrander-Stumpel Connie C   Héron Delphine D   Mignot Cyril C   Garavaglia Barbara B   Bhatia Kailash K   Hardy John J   Strom Tim M TM   Boddaert Nathalie N   Houlden Henry H HH   Kurian Manju A MA   Meitinger Thomas T   Prokisch Holger H   Hayflick Susan J SJ  

American journal of human genetics 20121121 6

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 ear  ...[more]

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