Clinical Use of Next-Generation Sequencing in the Diagnosis of Wilson’s Disease

Németh, Dániel; Árvai, Kristóf; Horváth, Péter; Kósa, János P.; Tobiás, Bálint; Balla, Bernadett; Folhoffer, Anikó; Krolopp, A; Lakatos, Péter; Szalay, Ferenç

doi:10.1155/2016/4548039

Cited by 15 publications

(7 citation statements)

References 18 publications

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“…Next generation sequencing (NGS) appeared a few years ago and revolutionized the genetic approach. As the great number of disease-causing ATP7B gene mutations may cause a real diagnostic challenge, NGS is rapidly providing a time-saving, cost-effective method for full sequencing of the whole ATP7B gene compared to the traditional Sanger sequencing (110). Russian authors estimated the price for comprehensive analysis of 1,000 samples for middle-sized gene (3,155 bp of coding sequence) as 6.2 US dollars per sample (111).…”

Section: Take Advantage Of Advances In Genetics Methodsmentioning

confidence: 99%

Challenges in the diagnosis of Wilson disease

Poujois

2019

Ann. Transl. Med

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The understanding and management of Wilson disease (WD) have dramatically improved since the first description of the disease by K. Wilson more than a century ago. However, the persistent long delay between the first symptoms and diagnosis emphasizes challenges in diagnosing earlier this copper overload disorder. As a treatable disease, WD should be detected early in the course of the disease by any health professionals at any care level, but the rare prevalence of the disease explains the lack of awareness of referring physicians. The most important challenge is to train physicians to recognize atypical or rare symptoms of WD that will lead to discuss the diagnosis more systematically. Atypia can come from the age of onset, the liver [non-alcoholic steatohepatitis (NASH) presentation], the central or peripheral nervous system (neuropathy, epilepsy, sleep disorders…) or may be due to lesions of other organs (renal manifestations, osteo-articular disorders or endocrine disturbances). Isolated biological anomalies, rare radiological findings or inadequate interpretation of copper test may also lead to misdiagnosis. The second challenge is to confirm the diagnosis faster and more effectively so as not to delay the initiation of treatment, and expand family screening as the genetic prevalence is higher than previously expected. Generalization of the exchangeable copper assay and the next generation sequencing (NGS) are two promising ways to overcome this ultimate challenge. By drawing attention to the earliest and rare symptoms and to new biomarkers and diagnostic tools, we hope that this article will increase diagnostic awareness and reduce delays so that patients can start their treatment earlier in the course of the illness and thus have a better disease prognosis.

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Section: Take Advantage Of Advances In Genetics Methodsmentioning

confidence: 99%

Challenges in the diagnosis of Wilson disease

Poujois

2019

Ann. Transl. Med

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“…Recently, next-generation sequencing (NGS) has emerged as a technique that can elucidate many of these cases. 33 Epigenetic factors causing genomic imprinting and other genetic disorders that mimic WD may also be considered. The large number of different mutations in patients with very different clinical features does not yet allow to establish clear genotype-phenotype associations.…”

Section: Discussionmentioning

confidence: 99%

Wilson disease: the diagnostic challenge and treatment outcomes in a series of 262 cases

Deguti,

Araujo,

Terrabuio

et al. 2024

Arq Neuropsiquiatr

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Background Wilson disease (WD) is an autosomal recessive disorder that leads to organ toxicity due to copper overload. Early diagnosis is complicated by the rarity and diversity of manifestations. Objective To describe the diagnostic features and response to treatment in our cohort of WD patients. Methods This was a retrospective analysis of 262 WD patients stratified by clinical presentation, complementary exams, ATP7B genotyping, and response to treatment. Results Symptoms occurred at an average age of 17.4 (7–49) years, and patients were followed up for an average of 9.6 (0–45) years. Patients presented mainly with hepatic (36.3%), neurologic (34.7%), and neuropsychiatric (8.3%) forms. Other presentations were hematologic, renal, or musculoskeletal, and 16.8% of the patients were asymptomatic. Kayser-Fleischer rings occurred in 78.3% of the patients, hypoceruloplasminemia in 98.3%, and elevated cupruria/24h in 73.0%, with an increase after D-penicillamine in 54.0%. Mutations of the ATP7B gene were detected in 84.4% of alleles. Brain magnetic resonance imaging showed abnormalities in the basal ganglia in 77.7% of patients. D-penicillamine was the first choice in 93.6% of the 245 patients, and 21.1% of these patients were switched due to adverse effects. The second-line therapies were zinc and trientine. The therapeutic response did not differ significantly between the drugs (p = 0.2). Nine patients underwent liver transplantation and 82 died. Conclusion Wilson disease is diagnosed at a late stage, and therapeutic options are limited. In people under 40 years of age with compatible manifestations, WD could be considered earlier in the differential diagnosis. There is a need to include ATP7B genotyping and therapeutic alternatives in clinical practice.

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“…Therefore, NGS would be effective for the rapid molecular diagnosis of WD. [ 22 ] Additionally, since the clinical and biochemical phenotypes of our affected sibs had indicated the specific disorder WD, a relative limited targeted NGS was performed with an economic consideration, instead of whole-exome sequencing (WES) or whole-genome sequencing (WGS). However, if there is no sign or biochemical phenotype indicating some specific genetic disorder for a patient with isolated POA, WES or WGS would be more helpful to reveal the pathogenic sequence variants.…”

Section: Discussionmentioning

confidence: 99%