Diagnostic yield and clinical utility of whole exome sequencing using an automated variant prioritization system, <scp>EVIDENCE</scp>

Seo, Go Hun; Kim, Sang Woo; Choi, In Hee; Park, Jung young; Lee, Jungsul; Kim, Sehwan; Won, Dhong gun; Oh, Arum; Lee, Yena; Choi, Jae-Hoon; Lee, Hajeong; Kang, Hee Gyung; Cho, Hee Yeon; Cho, Min Hyun; Kim, Yoon Jeon; Yoon, Young Hee; Eun, Baik Lin; Desnick, Robert J.; Keum, Changwon; Lee, Beom Hee

doi:10.1111/cge.13848

Cited by 84 publications

(62 citation statements)

References 38 publications

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“…Among the 376 children with neurological symptoms who underwent WES, the diagnostic yield of WES for these cohort were 42.7% [10] and four patients (1.1%) were diagnosed with actionable neurologic disorders with precision treatment (Table 1). , and a head circumference of 30.5 cm (SD, −3.12).…”

Section: Resultsmentioning

confidence: 99%

“…The streamlined, automated variant prioritization software system, termed EVIDENCE (3bilion Inc., Seoul, Korea) [ 10 ] used to identify the candidate variants is represented in Figure 1 . The software program analyses over 100,000 variants, according to ACMG guidelines, prioritizes the variants based on each phenotype of each patient and interprets these variants accurately and consistently.…”

Section: Methodsmentioning

confidence: 99%

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Clinical Application of Whole Exome Sequencing to Identify Rare but Remediable Neurologic Disorders

Kim

Yum

Seo

et al. 2020

JCM

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Background: The aim of this study was to describe the application of whole exome sequencing (WES) in the accurate genetic diagnosis and personalized treatment of extremely rare neurogenetic disorders. Methods: From 2017 to 2019, children with neurodevelopmental symptoms were evaluated using WES in the pediatric neurology clinic and medical genetics center. The clinical presentation, laboratory findings including the genetic results from WES, and diagnosis-based treatment and outcomes of the four patients are discussed. Results: A total of 376 children with neurodevelopmental symptom were evaluated by WES, and four patients (1.1%) were diagnosed with treatable neurologic disorders. Patient 1 (Pt 1) showed global muscle hypotonia, dysmorphic facial features, and multiple anomalies beginning in the perinatal period. Pt 1 was diagnosed with congenital myasthenic syndrome 22 of PREPL deficiency. Pt 2 presented with hypotonia and developmental arrest and was diagnosed with autosomal recessive dopa-responsive dystonia due to TH deficiency. Pt 3, who suffered from intractable epilepsy and progressive cognitive decline, was diagnosed with epileptic encephalopathy 47 with a heterozygous FGF12 mutation. Pt 4 presented with motor delay and episodic ataxia and was diagnosed with episodic ataxia type II (heterozygous CACNA1A mutation). The patients’ major neurologic symptoms were remarkably relieved with pyridostigmine (Pt 1), levodopa (Pt 2), sodium channel blocker (Pt 3), and acetazolamide (Pt 4), and most patients regained developmental milestones in the follow-up period (0.4 to 3 years). Conclusions: The early application of WES helps in the identification of extremely rare genetic diseases, for which effective treatment modalities exist. Ultimately, WES resulted in optimal clinical outcomes of affected patients.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Clinical Application of Whole Exome Sequencing to Identify Rare but Remediable Neurologic Disorders

Kim

Yum

Seo

et al. 2020

JCM

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“…Variant calling, annotation, and prioritization were performed as previously described. [ 19 ] In brief, the similarity between patient's phenotype and symptoms associated with disease caused by prioritized variants according to the American College of Medical Genetics (ACMG) guidelines [ 20 , 21 ] was integrated and automated by all computational process. [ 19 ]…”

Section: Methodsmentioning

confidence: 99%

Diagnosis of Schaaf-Yang syndrome in Korean children with developmental delay and hypotonia

Ahn

Seo

et al. 2020

Medicine

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Schaaf-Yang syndrome (SYS) is a recently identified disorder caused by a loss-of-function mutation in a maternally imprinted gene, MAGEL2 , at 15q11.2q13. Due to its extreme rarity and wide range of clinical severity, clinical suspicion is difficult for a physician. In the current study, its frequency among the Korean pediatric patients with developmental delay (DD) or intellectual disability (ID) was assessed. As the first report of Korean patients with SYS, our study aims to increase the awareness of this condition among the physicians taking care of the pediatric patients with DD/ID and hypotonia. The patients diagnosed with SYS by whole-exome sequencing (WES) among the 460 Korean pediatric patients with DD/ID were included, and their clinical and molecular features were reviewed. Four patients (0.9%) were diagnosed with SYS. Profound DD (4 patients), multiple anomalies including joint contractures and facial dysmorphism (4 patients), generalized hypotonia (3 patients), and severe respiratory difficulty requiring mechanical ventilation (3 patients) were noted in most cases, similar to those in previous reports. Sleep apnea (2 patients), autistic features (2 patients), a high grade of gastroesophageal reflux (1 patient), and seizures (1 patient) were found as well. A total of 3 different truncating MAGEL2 mutations were identified. A previously-reported mutation, to be the most common one, c.1996dupC, was found in 2 patients. The other 2 mutations, c.2217delC and c.3449_3450delTT were novel mutations. As MAGEL2 is maternally imprinted, 2 patients had inherited the MAGEL2 mutation from their respective healthy fathers. SYS is an extremely rare cause of DD/ID. However, hypotonia, joint contractures, profound DD/ID and facial dysmorphism are the suggestive clinical features for SYS. As a maternally imprinted disorder, it should be reminded that SYS may be inherited in form of a mutation from a healthy father.

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“…As a matter of fact, such an application is more practical for diagnosis because we need to discover the disease-causing variant from a large number of missense mutations found in the genome of patients. We checked the cases of rare disease patients, and gathered missense variants found in the genome of 107 patients who were diagnosed based on the ACMG guideline 36 . The disease-causing variants confirmed by medical doctors were annotated as positive samples while other missense variants from those patients were curated as negative samples.…”

Section: Patients Data In Diagnosis Casesmentioning

confidence: 99%

3Cnet: Pathogenicity prediction of human variants using knowledge transfer with deep recurrent neural networks

Won¹,

Lee²

2020

Preprint

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Thanks to the improvement of New Generation Sequencing (NGS), genome-based diagnosis for rare disease patients become possible. However, accurate interpretation of human variants requires massive amount of knowledge gathered from previous researches and clinical cases. Also, manual analysis for each variant in the genome of patients takes enormous time and effort of clinical experts and medical doctors. Therefore, to reduce the cost of diagnosis, various computational tools have been developed for the pathogenicity prediction of human variants. Nevertheless, there has been the circularity problem of conventional tools, which leads to the overlap of training data and eventually causes overfitting of algorithms. In this research, we developed a pathogenicity predictor, named as 3Cnet, using deep recurrent neural networks which analyzes the amino-acid context of a missense mutation. 3Cnet utilizes knowledge transfer of evolutionary conservation to train insufficient clinical data without overfitting. The performance comparison clearly shows that 3Cnet can find the true disease-causing variant from a large number of missense variants in the genome of a patient with higher sensitivity (recall = 13.9 %) compared to other prediction tools such as REVEL (recall = 7.5 %) or PrimateAI (recall = 6.4 %). Consequently, 3Cnet can improve the diagnostic rate for patients and discover novel pathogenic variants with high probability.

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Diagnostic yield and clinical utility of whole exome sequencing using an automated variant prioritization system, EVIDENCE

Cited by 84 publications

References 38 publications

Clinical Application of Whole Exome Sequencing to Identify Rare but Remediable Neurologic Disorders

Clinical Application of Whole Exome Sequencing to Identify Rare but Remediable Neurologic Disorders

Diagnosis of Schaaf-Yang syndrome in Korean children with developmental delay and hypotonia

3Cnet: Pathogenicity prediction of human variants using knowledge transfer with deep recurrent neural networks

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