Exome Sequencing Reveals A Novel Wdr45 Frameshift Mutation And Inherited Polr3a Heterozygous Variants In A Female With A Complex Phenotype And Mixed Brain Mri Findings

Title

Exome Sequencing Reveals A Novel Wdr45 Frameshift Mutation And Inherited Polr3a Heterozygous Variants In A Female With A Complex Phenotype And Mixed Brain Mri Findings

Creator

Khalifa M; Naffaa L

Publisher

European Journal of Medical Genetics

Date

2015
2015-08

Description

WDR45 and POLR3A are newly recognized genes; each is associated with a distinct neurodegenerative disease. WDR45 is an X-linked gene associated with a dominant form of Neurodegeneration with Brain Iron Accumulation (NBIA), manifested by progressive disabilities, dystonia, cognitive decline, spastic paraplegia, neuropsychiatric abnormalities and iron deposition in the basal ganglia on brain imaging. POLR3A, on the other hand, is an autosomal gene, and its mutations cause a recessive form of a hypomyelination with leukodystrophy disease, also known as 4H syndrome, characterized by congenital Hypomyelination with thinning of the corpus callosum, Hypodontia and Hypogonadotropic Hypogonadism. We report on a female child with severe intellectual disability, aphasia, short stature, ataxia, failure to thrive and structural brain abnormalities. Brain MRI obtained in late infancy showed hypomyelination involving the central periventricular white matter and thinning of the corpus callosum with no evidence of iron accumulation. Brain MRI obtained in childhood showed stable hypomyelination, with progressive iron accumulation in the basal ganglia, in particular in the globus pallidus and substantia nigra. Whole Exome Sequencing (WES) identified a novel WDR45 frameshift deleterious mutation in Exon 9 (c.587-588del) and also revealed three POLR3A missense heterozygous variants. The first is a maternally inherited novel missense variant in exon 4 (c.346A > G). Exon 13 carried two heterozygous missense variants, a maternally inherited variant (c.1724A > T) and a paternally inherited variant (1745G > A). These variants are considered likely damaging. The patient's complex clinical phenotype and mixed brain MRI findings might be attributed to the confounding effects of the expression of these two mutant genes. (C) 2015 Elsevier Masson SAS. All rights reserved.

Subject

4H syndrome; accumulation; atp13a2 mutations; clinical spectrum; Demyelinating disease; diabetes-mellitus; gene; Genetics & Heredity; hallervorden-spatz-syndrome; hypogonadism; iron; Leukodystrophy; Leukodystrophy; NBIA; neurodegeneration; POLR3A; spastic paraplegia spg35; WDR45; Whole exome sequencing

Format

Journal Article or Conference Abstract Publication

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Rights

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

Pages

381-386

Issue

8

Volume

58

Citation

Khalifa M; Naffaa L, “Exome Sequencing Reveals A Novel Wdr45 Frameshift Mutation And Inherited Polr3a Heterozygous Variants In A Female With A Complex Phenotype And Mixed Brain Mri Findings,” NEOMED Bibliography Database, accessed July 31, 2021, https://neomed.omeka.net/items/show/10454.

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