Diagnostic Yield and Treatment Impact of Targeted Exome Sequencing in Early-onset Epilepsy

AbstractBackgroundTo examine the impact on diagnosis, treatment and cost with early use of targeted whole-exome sequencing (WES) in early-onset epilepsy.MethodsWES was performed on 50 patients with early-onset epilepsy (≤ 5 years) of unknown cause. Patients were classified as retrospective (epilepsy diagnosis > 6 months) or prospective (epilepsy diagnosis < 6 months). WES was performed on an Ion ProtonTM and variant reporting was restricted to the sequences of 565 known epilepsy genes. Diagnostic yield and time to diagnosis were calculated. An analysis of cost and impact on treatment was also performed.ResultsA likely/definite diagnosis was made in 17/50 patients (34%) with immediate treatment implications in 8/17 (47%). A possible diagnosis was identified in 9 additional patients (18%) for whom supporting evidence is pending. Time from epilepsy onset to genetic diagnosis was faster when WES was performed early in the diagnostic process (mean: 143 days prospective versus 2,172 days retrospective). Costs of prior negative tests averaged $8,344 in the retrospective group, suggesting savings of up to $5,110 per patient.InterpretationThese results support the clinical utility and potential cost-effectiveness of using targeted WES early in the diagnostic workup of patients with unexplained early-onset epilepsy. The costs and clinical benefits are likely to continue to improve. Advances in precision medicine and further studies regarding impact on long-term clinical outcome will be important.

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Technological Improvements in the Genetic Diagnosis of Rett Syndrome Spectrum Disorders

International Journal of Molecular Sciences ◽

10.3390/ijms221910375 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10375

Author(s):

Clara Xiol ◽

Maria Heredia ◽

Ainhoa Pascual-Alonso ◽

Alfonso Oyarzabal ◽

Judith Armstrong

Keyword(s):

Exome Sequencing ◽

Rett Syndrome ◽

Diagnostic Yield ◽

Neurodevelopmental Disorder ◽

Genetic Diagnosis ◽

Phenotypic Characterization ◽

Diagnostic Process ◽

The Past ◽

Gene Testing ◽

Spectrum Disorders

Rett syndrome (RTT) is a severe neurodevelopmental disorder that constitutes the second most common cause of intellectual disability in females worldwide. In the past few years, the advancements in genetic diagnosis brought by next generation sequencing (NGS), have made it possible to identify more than 90 causative genes for RTT and significantly overlapping phenotypes (RTT spectrum disorders). Therefore, the clinical entity known as RTT is evolving towards a spectrum of overlapping phenotypes with great genetic heterogeneity. Hence, simultaneous multiple gene testing and thorough phenotypic characterization are mandatory to achieve a fast and accurate genetic diagnosis. In this review, we revise the evolution of the diagnostic process of RTT spectrum disorders in the past decades, and we discuss the effectiveness of state-of-the-art genetic testing options, such as clinical exome sequencing and whole exome sequencing. Moreover, we introduce recent technological advancements that will very soon contribute to the increase in diagnostic yield in patients with RTT spectrum disorders. Techniques such as whole genome sequencing, integration of data from several “omics”, and mosaicism assessment will provide the tools for the detection and interpretation of genomic variants that will not only increase the diagnostic yield but also widen knowledge about the pathophysiology of these disorders.

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Exome sequencing in paediatric patients with movement disorders

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-01688-6 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Anna Ka-Yee Kwong ◽

Mandy Ho-Yin Tsang ◽

Jasmine Lee-Fong Fung ◽

Christopher Chun-Yu Mak ◽

Kate Lok-San Chan ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Movement Disorders ◽

Rare Variants ◽

Diagnostic Yield ◽

Neurological Diseases ◽

Genetic Diagnosis ◽

Potential Treatment ◽

Paediatric Patients ◽

Whole Exome

Abstract Background Movement disorders are a group of heterogeneous neurological diseases including hyperkinetic disorders with unwanted excess movements and hypokinetic disorders with reduction in the degree of movements. The objective of our study is to investigate the genetic etiology of a cohort of paediatric patients with movement disorders by whole exome sequencing and to review the potential treatment implications after a genetic diagnosis. Results We studied a cohort of 31 patients who have paediatric-onset movement disorders with unrevealing etiologies. Whole exome sequencing was performed and rare variants were interrogated for pathogenicity. Genetic diagnoses have been confirmed in 10 patients with disease-causing variants in CTNNB1, SPAST, ATP1A3, PURA, SLC2A1, KMT2B, ACTB, GNAO1 and SPG11. 80% (8/10) of patients with genetic diagnosis have potential treatment implications and treatments have been offered to them. One patient with KMT2B dystonia showed clinical improvement with decrease in dystonia after receiving globus pallidus interna deep brain stimulation. Conclusions A diagnostic yield of 32% (10/31) was reported in our cohort and this allows a better prediction of prognosis and contributes to a more effective clinical management. The study highlights the potential of implementing precision medicine in the patients.

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Diagnostic Yield and Treatment Impact of Targeted Exome Sequencing in Early-Onset Epilepsy

Frontiers in Neurology ◽

10.3389/fneur.2019.00434 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 19

Author(s):

Michelle Demos ◽

Ilaria Guella ◽

Conrado DeGuzman ◽

Marna B. McKenzie ◽

Sarah E. Buerki ◽

...

Keyword(s):

Exome Sequencing ◽

Early Onset ◽

Diagnostic Yield ◽

Targeted Exome Sequencing

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Whole Exome Sequencing in Neurogenetic Diagnostic Odysseys: An Argentinian Experience

10.1101/060319 ◽

2016 ◽

Cited By ~ 1

Author(s):

M Córdoba ◽

SA Rodriguez-Quiroga ◽

PA Vega ◽

H Amartino ◽

C Vázquez-Dusefante ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Low Income ◽

Clinical Management ◽

Diagnostic Yield ◽

Genetic Disorders ◽

Potential Cost ◽

Low Income Country ◽

Whole Exome ◽

Neurogenetic Disorders

ABSTRACTClinical variability is a hallmark of neurogenetic disorders. They involve widespread neurological entities such as neuropathies, ataxias, myopathies, mitochondrial encephalopathies, leukodystrophies, epilepsy and intellectual disabilities. Despite the use of considerable time and resources, the diagnostic yield in this field has been disappointingly low. This etiologic search has been called a “diagnostic odyssey” for many families. Whole exome sequencing (WES) has proved to be useful across a variety of genetic disorders, simplifying the odyssey of many patients and their families and leading to subsequent changes in clinical management in a proportion of them. Although a diagnostic yield of about 30% in neurogenetic disorders can be extrapolated from the results of large series that have included other medical conditions as well, there are not specific reports assessing its utility in a setting such as ours: a neurogeneticist led academic group serving in a low-income country. Herein, we report on a series of our first 40 consecutive cases that were selected for WES in a research-based neurogenetics laboratory. We demonstrated the clinical utility of WES in our patient cohort, obtaining a diagnostic yield of 40% (95% CI, 24.8%-55.2%), describing cases in which clinical management was altered, and suggesting the potential cost-effectiveness of WES as a single test by examining the number and types of tests that were performed prior to WES which added up to a median cost of $3537.6 ($2892 to $5084) for the diagnostic odysseys experienced by our cohort.

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Delineation of molecular findings by whole exome sequencing for suspected cases of paediatric-onset mitochondrial diseases in the Southern Chinese population

10.21203/rs.3.rs-23585/v2 ◽

2020 ◽

Author(s):

Mandy Ho-Yin Tsang ◽

Anna Ka-Yee Kwong ◽

Kate Lok-San Chan ◽

Jasmine Lee-Fong Fung ◽

Mullin Ho-Chung Yu ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Chinese Population ◽

Founder Mutation ◽

Diagnostic Yield ◽

Genetic Diagnosis ◽

Mitochondrial Diseases ◽

Chinese Patients ◽

Southern Chinese ◽

Whole Exome

Abstract BackgroundMitochondrial diseases (MDs) are a group of clinically and genetically heterogeneous disorders characterized by defects in oxidative phosphorylation. Since clinical phenotypes of MDs may be non-specific, genetic diagnosis is crucial for guiding disease management. In the current study, whole-exome sequencing (WES) was performed for our paediatric-onset MD cohort of a Southern Chinese origin, with the aim of identifying key disease-causing variants in the Chinese patients with MDs.MethodsWe recruited Chinese patients who had paediatric-onset MDs and a minimum mitochondrial disease criteria (MDC) score of 3. Patients with positive target gene or mitochondrial DNA sequencing results were excluded. WES was performed, variants with population frequency ≤1% were analysed for pathogenicity on the basis of the American College of Medical Genetics and Genomics guidelines.ResultsSixty-six patients with pre-biopsy MDC scores of 3–8 were recruited. The overall diagnostic yield was 35% (23/66). Eleven patients (17%) were found to have mutations in MD-related genes, with COQ4 having the highest mutation rate owing to the Chinese-specific founder mutation (4/66, 6%). Twelve patients (12/66, 18%) had mutations in non-MD-related genes: ATP1A3 (n=3, two were siblings), ALDH5A1 , ARX , FA2H , KCNT1 , LDHD , NEFL , NKX2-2 , TBCK , and WAC.ConclusionsWe confirmed that the COQ4 :c.370G>A, p.(Gly124Ser) variant was a recurrent founder mutation among the Southern Chinese population. Screening for this mutation should therefore be considered while diagnosing Chinese patients suspected to have MDs. Furthermore, WES has proven to be useful in detecting variants in patients suspected to have MDs because it helps to obtain an unbiased and precise genetic diagnosis for these diseases, which are genetically heterogeneous.

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P.109 Diagnostic Yield of Targeted Exome Sequencing in West Syndrome

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2021.385 ◽

2021 ◽

Vol 48 (s3) ◽

pp. S50-S50

Author(s):

M Parfyonov ◽

I Guella ◽

DM Evans ◽

S Adam ◽

C DeGuzman ◽

...

Keyword(s):

Exome Sequencing ◽

Genetic Heterogeneity ◽

High Throughput Sequencing ◽

De Novo ◽

Diagnostic Yield ◽

Genetic Diagnosis ◽

West Syndrome ◽

Global Developmental Delay ◽

Targeted Exome Sequencing ◽

Ion Proton

Background: West syndrome (WS) is characterized by the onset of epileptic spasms usually within the first year of life. Global developmental delay with/without regression is common. Advances in high-throughput sequencing have supported the genetic heterogeneity of this condition. To better understand the genetic causes of this disorder, we investigated the results of targeted exome sequencing in 29 patients with WS. Methods: Whole exome sequencing (WES) was performed on an Ion ProtonTM and variant reporting was restricted to sequences of 620 known epilepsy genes. Diagnostic yield and treatment impact are described for 29 patients with WS. Results: A definitely/likely diagnosis was made in 10 patients (34%), which included 10 different genes (ALG13, PAFAH1B1, SLC35A2, DYNC1H1, ADSL, DEPDC5, ARX, CDKL5, SCN8A, STXBP1) known to be associated with epilepsy or WS. Most variants were de novo dominant (X-linked/autosomal) except for ARX (X-linked recessive) and ADSL (autosomal recessive). 4 out of 10 (40%) had a genetic diagnosis with potential treatment implications. Conclusions: These results emphasize the genetic heterogeneity of WS. The high diagnostic yield, along with the significant genetic variability, and the potential for treatment impact, supports the early use of this testing in patients with unexplained WS.

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Delineation of molecular findings by whole exome sequencing for suspected cases of paediatric-onset mitochondrial diseases in the Southern Chinese population

10.21203/rs.3.rs-23585/v1 ◽

2020 ◽

Author(s):

Mandy Ho-Yin Tsang ◽

Anna Ka-Yee Kwong ◽

Kate Lok-San Chan ◽

Jasmine Lee-Fong Fung ◽

Mullin Ho-Chung Yu ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Chinese Population ◽

Founder Mutation ◽

Diagnostic Yield ◽

Genetic Diagnosis ◽

Mitochondrial Diseases ◽

Chinese Patients ◽

Southern Chinese ◽

Whole Exome

Abstract Background Mitochondrial diseases (MDs) are a group of clinically and genetically heterogeneous disorders characterized by defects in oxidative phosphorylation. Since clinical phenotypes of MDs may be non-specific, genetic diagnosis is crucial for guiding disease management. In the current study, whole-exome sequencing (WES) was performed for our paediatric-onset MD cohort of a Southern Chinese origin, with the aim of identifying key disease-causing variants in the Chinese patients with MDs.Methods We recruited Chinese patients who had paediatric-onset MDs and a minimum mitochondrial disease criteria (MDC) score of 3. Patients with positive target gene or mitochondrial DNA sequencing results were excluded. WES was performed, variants with population frequency ≤1% were analysed for pathogenicity on the basis of the American College of Medical Genetics and Genomics guidelines.Results Sixty-six patients with pre-biopsy MDC scores of 3–8 were recruited. The overall diagnostic yield was 35% (23/66). Eleven patients (17%) were found to have mutations in MD-related genes, with COQ4 having the highest mutation rate owing to the Chinese-specific founder mutation (4/66, 6%). Twelve patients (12/66, 18%) had mutations in non-MD-related genes: ATP1A3 (n=3, two were siblings), ALDH5A1, ARX, FA2H, KCNT1, LDHD, NEFL, NKX2-2, TBCK, and WAC.Conclusions We confirmed that the COQ4:c.370G>A, p.(Gly124Ser) variant was a recurrent founder mutation among the Southern Chinese population. Screening for this mutation should therefore be considered while diagnosing Chinese patients suspected to have MDs. Furthermore, WES has proven to be useful in detecting variants in patients suspected to have MDs because it helps to obtain an unbiased and precise genetic diagnosis for these diseases, which are genetically heterogeneous.

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Diagnostic yield and clinical effects of exome sequencing analysis in patients with early-onset scoliosis

The Lancet ◽

10.1016/s0140-6736(19)32415-8 ◽

2019 ◽

Vol 394 ◽

pp. S79

Author(s):

Sen Zhao ◽

Yuanqiang Zhang ◽

Weisheng Chen ◽

Shengru Wang ◽

Pengfei Liu ◽

...

Keyword(s):

Exome Sequencing ◽

Early Onset ◽

Diagnostic Yield ◽

Early Onset Scoliosis ◽

Clinical Effects ◽

Sequencing Analysis

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Simultaneous Detection of CNVs and SNVs Improves the Diagnostic Yield of Fetuses with Ultrasound Anomalies and Normal Karyotypes

Genes ◽

10.3390/genes11121397 ◽

2020 ◽

Vol 11 (12) ◽

pp. 1397

Author(s):

Qingwei Qi ◽

Yulin Jiang ◽

Xiya Zhou ◽

Hua Meng ◽

Na Hao ◽

...

Keyword(s):

Exome Sequencing ◽

Diagnostic Yield ◽

Simultaneous Detection ◽

Genetic Diagnosis ◽

Copy Number Variations ◽

Molecular Diagnostic ◽

Chromosomal Microarray ◽

Chromosomal Microarray Analysis ◽

Single Nucleotide Variants ◽

Sequential Approach

The routine assessment to determine the genetic etiology for fetal ultrasound anomalies follows a sequential approach, which usually takes about 6–8 weeks turnaround time (TAT). We evaluated the clinical utility of simultaneous detection of copy number variations (CNVs) and single nucleotide variants (SNVs)/small insertion-deletions (indels) in fetuses with a normal karyotype with ultrasound anomalies. We performed CNV detection by chromosomal microarray analysis (CMA) or low pass CNV-sequencing (CNV-seq), and in parallel SNVs/indels detection by trio-based clinical exome sequencing (CES) or whole exome sequencing (WES). Eight-three singleton pregnancies with a normal fetal karyotype were enrolled in this prospective observational study. Pathogenic or likely pathogenic variations were identified in 30 cases (CNVs in 3 cases, SNVs/indels in 27 cases), indicating an overall molecular diagnostic rate of 36.1% (30/83). Two cases had both a CNV of uncertain significance (VOUS) and likely pathogenic SNV, and one case carried both a VOUS CNV and an SNV. We demonstrated that simultaneous analysis of CNVs and SNVs/indels can improve the diagnostic yield of prenatal diagnosis with shortened reporting time, namely, 2–3 weeks. Due to the relatively long TAT for sequential procedure for prenatal genetic diagnosis, as well as recent sequencing technology advancements, it is clinically necessary to consider the simultaneous evaluation of CNVs and SNVs/indels to enhance the diagnostic yield and timely TAT, especially for cases in the late second trimester or third trimester.

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