Early onset developmental delay and epilepsy in pediatric patients with WDR45 variants

Hongbo Chen, Yanyan Qian, Sha Yu, Deyong Xiao, Xiao Guo, Qing Wang, Lili Hao, Kai Yan, Yulan Lu, Xinran Dong, Wenhao Zhou, Bingbing Wu, Shuizhen Zhou, Huijun Wang
European Journal of Medical Genetics 2018 July 6

BACKGROUND: Developmental delay (DD) is a neurological disorder that presents with defects in gross motor, fine motor, language and cognition functions. WD repeat domain 45 (WDR45) is one of the disease-causing genes of DD. Previously, WDR45 de novo mutations were reported in certain adult and pediatric patients due to iron accumulation.

CLINICAL REPORT: We report five pediatric female patients with DD and epilepsy. Their ages were below 3 years at the first consultation, and precise diagnoses were difficult based on the available clinical information and phenotype.

METHODS: Children with DD and/or epilepsy presenting to the molecular diagnostic center of Children's Hospital of Fudan University between May 2016 and May 2017 were enrolled. The patients and their parents were subjected to whole-exome sequencing (WES), and we characterized the phenotypes of the patients carrying WDR45 variants. Furthermore, we overexpressed the candidate variants in HeLa cells and evaluated their effect on autophagy through Western blot and immunofluorescence staining with confocal microscopy.

RESULTS: Five WDR45 de novo mutations, namely, c.19C > T (p.Arg7*), c.401G > C (p.Arg134Pro), c.503G > A (p.Gly168Glu), c.700C > T (p.Arg234*), and c.912delT (p.Ala305Leufs*25), were detected in 623 enrolled pediatric patients (274 females; 487 patients younger than 6 years). All five patients with WDR45 variants presented with DD and epilepsy. Compared with the control HeLa cells, the cells with the p. Arg134Pro and p. Gly168Glu missense mutations showed accumulation of LC3-containing autophagic structures and an abnormally enlarged cell volume, and Western blotting revealed a significant increase in LC3II/GAPDH.

CONCLUSION: The identification of WDR45 mutations provides further evidence that WES plays an important role in the diagnosis of neurological disorders with common phenotypes and that WDR45 mutations are associated with neurological disorders and are not very rare in Chinese female pediatric patients with DD and/or epilepsy. The diagnosis of patients with WDR45 mutations would enable more precise genetic counseling for the parents of these children.

Full Text Links

Find Full Text Links for this Article


You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read

Save your favorite articles in one place with a free QxMD account.


Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"