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.

Clinical application of whole-exome sequencing across clinical indications

“…Utilizing the power of our large data set, we were able to identify novel candidate genes in which multiple patients with similar phenotypes had rare variants predicted to result in loss of function, many of which were de novo. Access to this large number of cases has proven extremely valu- [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] As a result of our experience, we believe that candidate genes should be reported from WES analysis and shared in databases, such as GeneMatcher, so that clinicians, researchers, and clinical laboratories can be connected to facilitate more rapid dissemination of information and validation of novel disease genes. Our series is larger than previously reported clinical diagnostic series and has the power to begin to address the yield of WES for a large number of clinical indications.…”

Autophagy at the crossroads of catabolism and anabolism

“…Moreover, the loss of NCOA4 reduced the level of bioavailable intracellular iron in cells subjected to iron depletion and led to the profound accumulation of iron in splenic macrophages in vivo 44 . Defects in ferritin turnover may cause the neuro degenerative disorder static encephalopathy of childhood with neurodegeneration in adults (SENDA), which is characterized by the accumulation of iron deposits in basal ganglia due to mutations in the autophagy gene WD repeat domain phosphoinositide-interacting protein 4 (WDR45) 111,112 (TABLE 1). Overall, these results highlight the importance of autophagy for iron homeostasis and bioavailability, especially during iron depletion.…”

Early-onset epileptic encephalopathy as the initial clinical presentation of WDR45 deletion in a male patient

“…3 This low incidence of male cases has been attributed to male lethality and the existence of a few male carriers to somatic mosaicism. 2 Among published cases, 70% of patients suffered from epileptic seizures beginning after 3 months of age. 3,4 Early-onset epileptic encephalopathies (EOEE) form a group of severe epilepsies occurring in the first 3 months of life.…”