Extended genetic analysis of exome sequencing for primary hyperoxaluria in pediatric urolithiasis patients with hyperoxaluria

AbstractImportanceAccurate diagnosis of pediatric patients with complicated neurological problems demands a well-coordinated combination of robust genetic analytic capability and delicate clinical evaluation. It should be tested whether this challenge can be augmented by whole exome sequencing (WES).ObjectiveTo evaluate the utility of WES-based diagnosis and discovery of novel variants of undiagnosed patients with complex neurodevelopmental problems in a country with a centralized medical system.Design, setting, and participantsA cohort of 352 Korean patients, believed to cover a major portion of the entire country from July 2014 to April 2017, with a broad spectrum of neurodevelopmental disorders without any pathogenic variants revealed by conventional methods were evaluated by trio-based WES at Seoul National University Children’s Hospital.ExposuresWES of patients and parents and subsequent evaluation of genetic variants.Main outcomes and measuresGenetic variants from each patient were evaluated for known disease association and novel variants were assessed for possible involvement with neurodevelopment process.ResultsWe identified disease-causing variants, including newly discovered variants, in 57.4% of the probands, who had underwent a mean of 5.6 years of undiagnosed periods and visited mean of 2.3 tertiary hospitals. The cohort included 112 patients with variants that were previously reported as pathogenic (31.8%), 16 patients with copy number variants (4.5%) and 27 patients with variants that were associated with different clinical symptoms (7.7%). We also discovered potentially pathogenic variants from 47 patients that required further functional assessments (13.4%) and demonstrated potential implications in neurodevelopmental disorders. Following the genetic analysis, we provided more precise treatments to selected patients. A few clinical vignettes are presented that illuminate the potential diagnostic pitfalls that one could have encountered without this approach.Conclusions and relevanceOur results highlight the utility of WES-based diagnosis for improved patient care in a country with a centralized medical system and discovery of novel pathophysiology mechanisms.Key pointsQuestionWhat is the advantage of whole exome sequencing based diagnosis of pediatric neurology patients with unknown rare symptoms in a large tertiary clinic in a country with a centralized medical system?FindingsWhole exome sequencing of 352 Korean patients, with a mean of 5.7 years of undiagnosed period, yielded 44.0% of conservative diagnostic yield. A number of cases were directly benefitted by trio-based WES via termination of diagnostic odyssey, genetic counseling for next offspring, or suggestion of more effective and customized treatment options.MeaningWe report on the establishment of a national-level whole exome-based diagnosis system, with emphasis on deliberate integration of clinical interpretation and genetic analysis. Whole exome sequencing should be a choice of diagnostic tools for pediatric neurologic patients with ambiguous symptoms.

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GENE-30. PRELIMINARY STUDY ON WHOLE-EXOME SEQUENCING TECHNOLOGY IN THE GENETIC ANALYSIS OF PEDIATRIC PATIENTS WITH GLIOMAS

Neuro-Oncology ◽

10.1093/neuonc/noz175.432 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi104-vi104

Author(s):

Mingyao Lai ◽

Juan Li ◽

Junjie Zhen ◽

jiangfen zhou ◽

Qingjun Hu ◽

...

Keyword(s):

Genetic Analysis ◽

Signaling Pathways ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Pediatric Patients ◽

Genetic Mutation ◽

Pleomorphic Xanthoastrocytoma ◽

Pathological Examination ◽

Sequencing Technology ◽

Whole Exome

Abstract OBJECTIVE To analyze the genes related to the signaling pathways in pediatric gliomas and drug-related genes with whole-exome sequencing technology. METHODS The tumor tissues and matched blood samples of 17 enrolled patients were detected with whole-exome sequencing technology. There were 3 cases of diffuse midline gliomas, 2 cases of childhood glioblastomas, 3 cases of disffuse astrocytoma, 1 case of pleomorphic xanthoastrocytoma, 1 case of ganglioglioma, 6 cases of anaplastic ependymoma and 1 case of ependymoma in this study. All the enrolled patients who were no more than 14 years old received surgery in the Department of Neurosurgery, Guangdong Sanjiu Brain Hospital. The diagnosis was confirmed by pathological examination and the sample acquisition was approved by hospital ethics committee. RESULTS With the use of whole-exome sequencing technology, a total of 31 related genetic mutations were detected in 15 cases, while no genetic mutation was detected in the other 2 cases. The genes related to the signaling pathways in pediatric gliomas included ATRX, ASL1, BCOR, EP300, FGFR1, H3F3A, IGF1R, MED12, PIK3R1, PRKDC, RB1, SETD2, SMARCA4, SOX2, TGFBR2, and the drug-related genes included AKT1, BCL2, BRAF, BRCA2, CCND1, CCND2, CDK6, EGFR, FGF3, KRAS, MET, PDGFRA, PIK3CA, PTEN, TP53, TSC1. One patient only had genes related to the signaling pathways, and 14 patients had drug-related genes. CONCLUSION Applying whole-exome sequencing technology in the genetic analysis of pediatric patients with gliomas has remarkable guiding significance for revealing the mechanism of disease, searching for therapeutic targets and adopting individualized treatment, which can bring potential benefits to pediatric patients. However, more samples and further data analysis and verification are needed in future study.

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Targeted Exome Sequencing Identified a Novel USH2A Mutation in a Chinese Usher Syndrome Family

10.21203/rs.3.rs-16667/v1 ◽

2020 ◽

Author(s):

Dongjun Xing ◽

Huaiyu Zhou ◽

Rongguo Yu ◽

Linni Wang ◽

Liying Hu ◽

...

Keyword(s):

Optical Coherence Tomography ◽

Genetic Analysis ◽

Exome Sequencing ◽

Novel Mutation ◽

Usher Syndrome ◽

Syndrome Type ◽

Optical Coherence ◽

Targeted Exome Sequencing ◽

Usher Syndrome Type

Abstract Background To identify the gene mutation in a Chinese family with Usher syndrome type 2 and describe the clinical features. Methods A 23-year-old man complain of 10-year nyctalopia and a 3-year decline in visual acuity in both eyes accompanied by congenital dysaudia. To clarify the diagnosis, the clinical symptoms of the patient were observed and analysed in combination with comprehensive ophthalmologic examinations as well as genetic analysis(Targeted exome sequencing, TES). Results Typical clinical presentation of Usher syndrome on fundus features was found, which included a wax yellow-like disc, bone-spicule formations, and retinal vessel stenosis. Optical coherence tomography(OCT) and optical coherence tomography angiography (OCTA) showed loss of the ellipsoid zone and a reduction in paracaval vessel density in both eyes. Genetic analysis identified the presence of novel homozygote of c.8483_8486del (p.S2828fs) in USH2A, a gene responsible for Usher syndrome type 2 (OMIM:276901). This novel mutation in USH2A led to premature translation termination, resulting in the deletion of 19 fibronectin type 3 domains(FN3), which plays an important role in protein binding. Based on the clinical manifestations and genetic result, the patient was diagnosed with Usher syndrome type 2. Conclusions We found a novel mutation of c.8483_8486del in USH2A gene through TES techniques for 381 inherited retinal disease (IRD) related genes. The results of this study broaden the spectrum of mutations in Usher syndrome type 2 and suggest that the combination of TES molecular diagnosis and clinical information can help USH patients obtain a better diagnoses.

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Genetic Analysis of Korean Adult Patients with Nontuberculous Mycobacteria Suspected of Primary Ciliary Dyskinesia Using Whole Exome Sequencing

Yonsei Medical Journal ◽

10.3349/ymj.2021.62.3.224 ◽

2021 ◽

Vol 62 (3) ◽

pp. 224

Author(s):

Eun Hye Cho ◽

Chang-Seok Ki ◽

Sun Ae Yun ◽

Su-Young Kim ◽

Byung Woo Jhun ◽

...

Keyword(s):

Genetic Analysis ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Primary Ciliary Dyskinesia ◽

Nontuberculous Mycobacteria ◽

Adult Patients ◽

Whole Exome ◽

Korean Adult ◽

Ciliary Dyskinesia

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Hereditary Cushing’s syndrome caused by primary bilateral macronodular adrenal hyperplasia due to ARMC5 mutation with concomitant primary hyperparathyroidism: the first known case in Russia

Problems of Endocrinology ◽

10.14341/probl9712 ◽

2019 ◽

Vol 65 (2) ◽

pp. 89-94

Author(s):

Elizaveta O. Mamedova ◽

Evgeny V. Vasilyev ◽

Vasily M. Petrov ◽

Natalya S. Izmailova ◽

Svetlana A. Buryakina ◽

...

Keyword(s):

Family History ◽

Genetic Analysis ◽

Primary Hyperparathyroidism ◽

Exome Sequencing ◽

Clinical Case ◽

Suppressor Gene ◽

Heterozygous Mutation ◽

Adrenal Hyperplasia ◽

Whole Exome ◽

Mild Primary Hyperparathyroidism

Primary bilateral macronodular adrenal hyperplasia (PBMAH), a genetically heterogeneous disease, is a rare cause of Cushings syndrome. Until recently, few cases were attributed to mutations in known genes. However, in 2013, ARMC5, a newly discovered tumor suppressor gene, was identified. Further studies have shown that mutations in the ARMC5 gene are found in 2555% of all PBMAH cases. This article describes a clinical case of hereditary Cushings syndrome caused by PBMAH in a 37-year old patient. The patients family history is remarkable for the presence of Cushings syndrome and PBMAH in the patients mother. Bilateral adrenalectomy was performed as the treatment of choice. Genetic analysis using whole-exome sequencing confirmed the hereditary cause of the disease, revealing a germline heterozygous mutation in the ARMC5 gene. The patient also had concomitant mild primary hyperparathyroidism, which had not been observed before in genetic carriers with the ARMC5 mutation.

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Targeted exome sequencing identified a novel USH2A mutation in a Chinese Usher syndrome family: a case report

10.21203/rs.3.rs-16667/v6 ◽

2020 ◽

Author(s):

Dongjun Xing ◽

Huaiyu Zhou ◽

Rongguo Yu ◽

Linni Wang ◽

Liying Hu ◽

...

Keyword(s):

Optical Coherence Tomography ◽

Genetic Analysis ◽

Exome Sequencing ◽

Usher Syndrome ◽

Chinese Family ◽

Syndrome Type ◽

Optical Coherence ◽

Targeted Exome Sequencing ◽

Usher Syndrome Type

Abstract Background: Usher syndrome is a disease with a heterogeneous phenotype and genotype. Our purpose was to identify the gene mutation in a Chinese family with Usher syndrome type 2 and describe the clinical features.Case presentation: A 23-year-old man complained of a 10-year duration of nyctalopia and a 3-year decline in visual acuity of both eyes accompanied by congenital dysaudia. To clarify the diagnosis, the clinical symptoms were observed and analysed in combination with comprehensive ophthalmologic examinations as well as genetic analysis (targeted exome sequencing, TES). A typical clinical presentation of Usher syndrome of the fundus was found, including a waxy yellow-like disc, bone-spicule formations and retinal vessel stenosis. Optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) showed loss of the ellipsoid zone and a reduction in paracaval vessel density in both eyes. Genetic analysis identified a novel homozygous c.8483_8486del (p.Ser2828*) mutation in USH2A. The mutation resulted in premature termination of translation and caused the deletion of 19 fibronectin type 3 domains (FN3), transmembrane (TM) region and PDZ-binding motif domain, which play an important role in protein binding. After combining the clinical manifestations and genetic results, the patient was diagnosed with Usher syndrome type 2.Conclusion: We found a novel c.8483_8486del mutation in the USH2A gene through TES techniques. The results broaden the spectrum of mutations in Usher syndrome type 2 and suggest that a combination of clinical information and molecular diagnosis via TES could help Usher syndrome patients obtain a better diagnosis.

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