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Efficiency of exome sequencing for the molecular diagnosis of pseudoxanthoma elasticum.

ABSTRACT: The molecular etiology of pseudoxanthoma elasticum (PXE), an autosomal recessive connective tissue disorder, has become increasingly complex as not only mutations in ATP-binding cassette family C member 6 (ABCC6) but also ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) and gamma-glutamyl carboxylase (GGCX) can cause resembling phenotypes. Identification of modifier genes, such as vascular endothelial growth factor A, has further contributed to the molecular heterogeneity of PXE. In such heterogeneous diseases, next-generation sequencing (NGS) allows to perform mutation screening of several genes in a single reaction. We explored whole-exome sequencing (WES) as an efficient diagnostic tool to identify the causal mutations in ABCC6, GGCX, ENPP1, and vitamin K epoxide reductase complex, subunit 1 (VKORC1) in 16 PXE patients. WES identified a causal ABCC6 mutation in 30 out of 32 alleles and one GGCX mutation, whereas no causal mutations in ENPP1 or VKORC1 were detected. Exomes with insufficient reads (?20 depth) for the four genes and patients with single mutations were further evaluated by Sanger sequencing (SS), but no additional mutations were found. The potential of WES compared with targeted NGS is the ease to examine target genes and the opportunity to search for novel genes when targeted analysis is negative. Together with low cost, rapid and less laborious workflow, we conclude that WES complemented with SS can provide a tiered approach to molecular diagnostics of PXE.

SUBMITTER: Hosen MJ

PROVIDER: S-EPMC4378258 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Efficiency of exome sequencing for the molecular diagnosis of pseudoxanthoma elasticum.

Hosen Mohammad J MJ Van Nieuwerburgh Filip F Steyaert Wouter W Deforce Dieter D Martin Ludovic L Leftheriotis Georges G De Paepe Anne A Coucke Paul J PJ Vanakker Olivier M OM

The Journal of investigative dermatology 20140929 4

The molecular etiology of pseudoxanthoma elasticum (PXE), an autosomal recessive connective tissue disorder, has become increasingly complex as not only mutations in ATP-binding cassette family C member 6 (ABCC6) but also ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) and gamma-glutamyl carboxylase (GGCX) can cause resembling phenotypes. Identification of modifier genes, such as vascular endothelial growth factor A, has further contributed to the molecular heterogeneity of PXE. In su ...[more]

PMID: 25264593

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Project description:Pseudoxanthoma elasticum (PXE) is a genetic metabolic disease with autosomal recessive inheritance caused by mutations in the ABCC6 gene. The lack of functional ABCC6 protein leads to ectopic mineralization that is most apparent in the elastic tissues of the skin, eyes and blood vessels. The clinical prevalence of PXE has been estimated at between 1 per 100,000 and 1 per 25,000, with slight female predominance. The first clinical sign of PXE is almost always small yellow papules on the nape and sides of the neck and in flexural areas. The papules coalesce, and the skin becomes loose and wrinkled. The mid-dermal elastic fibers are short, fragmented, clumped and calcified. Dystrophic calcification of Bruch's membrane, revealed by angioid streaks, may trigger choroidal neovascularization and, ultimately, loss of central vision and blindness in late-stage disease. Lesions in small and medium-sized artery walls may result in intermittent claudication and peripheral artery disease. Cardiac complications (myocardial infarction, angina pectoris) are thought to be relatively rare but merit thorough investigation. Ischemic strokes have been reported. PXE is a metabolic disease in which circulating levels of an anti-mineralization factor are low. There is good evidence to suggest that the factor is inorganic pyrophosphate (PPi), and that the circulating low levels of PPi and decreased PPi/Pi ratio result from the lack of ATP release by hepatocytes harboring the mutant ABCC6 protein. However, the substrate(s) bound, transported or modulated by the ABCC6 protein remain unknown. More than 300 sequence variants of the ABCC6 gene have been identified. There is no cure for PXE; the main symptomatic treatments are vascular endothelial growth factor inhibitor therapy (for ophthalmic manifestations), lifestyle, lipid-lowering and dietary measures (for reducing vascular risk factors), and vascular surgery (for severe cardiovascular manifestations). Future treatment options may include gene therapy/editing and pharmacologic chaperone therapy.

Project description:ImportanceAcute retinopathy may partly explain variable disease manifestation and vision loss in patients with pseudoxanthoma elasticum (PXE). The diagnosis of this likely autoimmune process may inform patient counseling and treatment approaches.ObjectiveTo characterize acute retinopathy in patients with PXE as a disease manifestation that may be associated with profound visual impairment.Design, setting, and participantsThis single-center case series was conducted from May 2013 to October 2018. It used the patient database of the Department of Ophthalmology at the University of Bonn, a referral center for PXE in Germany. Patients at this center with genetically confirmed PXE and who met the inclusion criteria were included (n = 9). Patients underwent multimodal retinal imaging, including fundus photography, fundus autofluorescence (AF), optical coherence tomography (OCT), fluorescein angiography (FA), and indocyanine green angiography (ICGA); in select cases, electroretinography as well as antiretinal and anti-retinal pigment epithelium (RPE) antibody testing were also used.Main outcomes and measuresClinical presentation and disease course.ResultsNine patients (8 [89%] female; mean [range] age, 43 [19-55] years) with acute retinopathy were identified in a cohort of 167 consecutive patients with PXE (frequency of 5%). Symptoms ranged from light sensations or metamorphopsia to profound vision loss. Visual acuity was reduced in 6 patients (67%), ranging from a best-corrected visual acuity of 20/30 to perception of hand movements at manifestation. All patients revealed characteristic fundus features with temporary appearance of partly confluent outer retinal whitish dots at the posterior pole, which corresponded to areas of hyperautofluorescence on fundus AF, loss of the ellipsoid band on OCT, and associated scotomata. The FA and late-phase ICGA imaging showed associated hyperfluorescence and hypocyanescence. Electroretinography revealed a variable reduction of amplitudes. Changes were fully reversible within 1 month in 3 of 8 patients with available follow-up data. Of the remaining 5 patients, 3 had a prolonged and likely permanent vision loss (observation period, 1-64 months) mainly owing to central subretinal hyperreflective material originating from angioid streaks. In 4 (67%) of 6 tested, antiretinal and/or anti-RPE antibodies were detected.Conclusions and relevanceAcute retinopathy in patients with PXE may occur, with symptoms ranging from short-term, reversible alterations to irreversible vision loss; these findings contribute to understanding the variable ocular disease progression in PXE and provide insights into the autoimmune phenomena of the posterior pole.

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Efficiency of exome sequencing for the molecular diagnosis of pseudoxanthoma elasticum.

Publications

Efficiency of exome sequencing for the molecular diagnosis of pseudoxanthoma elasticum.

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