scholarly journals Personalised virtual gene panels reduce interpretation workload and maintain diagnostic rates of proband-only clinical exome sequencing for rare disorders

2021 ◽  
pp. jmedgenet-2020-107303
Author(s):  
Leslie Patricia Molina-Ramírez ◽  
Claire Kyle ◽  
Jamie M Ellingford ◽  
Ronnie Wright ◽  
Algy Taylor ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Gene Selection ◽  
Diagnostic Yield ◽  
Cost Effective ◽  
Gene Panel ◽  
Monogenic Disorders ◽  
Use Of Resources ◽  
Clinical Exome Sequencing ◽  
Cost Effective Approach ◽  
Gene Panels

PurposeThe increased adoption of genomic strategies in the clinic makes it imperative for diagnostic laboratories to improve the efficiency of variant interpretation. Clinical exome sequencing (CES) is becoming a valuable diagnostic tool, capable of meeting the diagnostic demand imposed by the vast array of different rare monogenic disorders. We have assessed a clinician-led and phenotype-based approach for virtual gene panel generation for analysis of targeted CES in patients with rare disease in a single institution.MethodsRetrospective survey of 400 consecutive cases presumed by clinicians to have rare monogenic disorders, referred on singleton basis for targeted CES. We evaluated diagnostic yield and variant workload to characterise the usefulness of a clinician-led approach for generation of virtual gene panels that can incorporate up to three different phenotype-driven gene selection methods.ResultsAbnormalities of the nervous system (54.5%), including intellectual disability, head and neck (19%), skeletal system (16%), ear (15%) and eye (15%) were the most common clinical features reported in referrals. Combined phenotype-driven strategies for virtual gene panel generation were used in 57% of cases. On average, 7.3 variants (median=5) per case were retained for clinical interpretation. The overall diagnostic rate of proband-only CES using personalised phenotype-driven virtual gene panels was 24%.ConclusionsOur results show that personalised virtual gene panels are a cost-effective approach for variant analysis of CES, maintaining diagnostic yield and optimising the use of resources for clinical genomic sequencing in the clinic.

scholarly journals Next-Generation Sequencing Gene Panels and “Solo” Clinical Exome Sequencing Applied in Structurally Abnormal Fetuses

2021 ◽  
pp. 1-11
Author(s):  
Montse Pauta ◽  
Berta Campos ◽  
Maria Segura-Puimedon ◽  
Gemma Arca ◽  
Alfons Nadal ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Exome Sequencing ◽  
Diagnostic Yield ◽  
Monogenic Disease ◽  
Chromosomal Microarray Analysis ◽  
Next Generation ◽  
Clinical Exome Sequencing ◽  
Gene Panels ◽  
Generation Sequencing ◽  
Structural Anomalies

<b><i>Objective:</i></b> The aim of the study was to assess the diagnostic yield of 2 different next-generation sequencing (NGS) approaches: gene panel and “solo” clinical exome sequencing (solo-CES), in fetuses with structural anomalies and normal chromosomal microarray analysis (CMA), in the absence of a known familial mutation. <b><i>Methodology:</i></b> Gene panels encompassing from 2 to 140 genes, were applied mainly in persistent nuchal fold/fetal hydrops and in large hyperechogenic kidneys. Solo-CES, which entails sequencing the fetus alone and only interpreting the Online Mendelian Inheritance in Man genes, was performed in multisystem or recurrent structural anomalies. <b><i>Results:</i></b> During the study period (2015–2020), 153 NGS studies were performed in 148 structurally abnormal fetuses with a normal CMA. The overall diagnostic yield accounted for 35% (53/153) of samples and 36% (53/148) of the fetuses. Diagnostic yield with the gene panels was 31% (15/49), similar to 37% (38/104) in solo-CES. <b><i>Conclusions:</i></b> A monogenic disease was established as the underlying cause in 35% of selected fetal structural anomalies by gene panels and solo-CES.

scholarly journals Assessing utility of clinical exome sequencing in diagnosis of rare idiopathic neurodevelopmental disorders in Indian population

2019 ◽  
Author(s):  
Harsh Sheth ◽  
Dhairya Pancholi ◽  
Riddhi Bhavsar ◽  
Ashraf U. Mannan ◽  
Aparna Ganapathy ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Neurological Disorders ◽  
Indian Population ◽  
De Novo ◽  
Diagnostic Yield ◽  
Neurological Diseases ◽  
Cost Effective ◽  
European Population ◽  
Clinical Exome Sequencing ◽  
Deep Phenotyping

Abstract Background: Neurological diseases are phenotypically and genotypically heterogeneous. Clinical exome sequencing (CES) has been shown to provide a high diagnostic yield for these disorders in the European population but remains to be demonstrated for the Indian population. Methods: A cohort of 19 idiopathic patients with neurological phenotypes, primarily intellectual disability and developmental delay, were recruited. CES covering 4620 genes was performed on all patients. Candidate variants were validated by Sanger sequencing. Results: CES in 19 patients provided identified 21 variants across 16 genes which have been associated with different neurological disorders. Fifteen variants were reported previously and 6 variants were novel to our study. Eleven patients were diagnosed with autosomal dominant de novo variants, 7 with autosomal recessive and 1 with X-linked recessive variants. CES provided definitive diagnosis to 10 patients, hence the diagnostic yield was 53%. Conclusion: Our study suggests that the diagnostic yield of CES in the Indian population is comparable to that reported in the European population. CES together with deep phenotyping could be a cost-effective way of diagnosing rare neurological disorders in the Indian population.

scholarly journals Exome sequencing has higher diagnostic yield compared to simulated disease-specific panels in children with suspected monogenic disorders

2018 ◽  
Vol 26 (5) ◽  
pp. 644-651 ◽  
Author(s):  
Oliver James Dillon ◽  
◽  
Sebastian Lunke ◽  
Zornitza Stark ◽  
Alison Yeung ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Diagnostic Yield ◽  
Monogenic Disorders ◽  
Simulated Disease ◽  
Disease Specific

scholarly journals Brief Report: Evaluating the Diagnostic Yield of Commercial Gene Panels in Autism

2022 ◽  
Author(s):  
Fiana Ní Ghrálaigh ◽  
Ellen McCarthy ◽  
Daniel N. Murphy ◽  
Louise Gallagher ◽  
Lorna M. Lopez
Keyword(s):  
Clinical Utility ◽  
Gene Selection ◽  
Diagnostic Yield ◽  
Genetic Evidence ◽  
Clinical Sequencing ◽  
Selection For ◽  
Gene Panels

AbstractAutism is a prevalent neurodevelopmental condition, highly heterogenous in both genotype and phenotype. This communication adds to existing discussion of the heterogeneity of clinical sequencing tests, “gene panels”, marketed for application in autism. We evaluate the clinical utility of available gene panels based on existing genetic evidence. We determine that diagnostic yields of these gene panels range from 0.22% to 10.02% and gene selection for the panels is variable in relevance, here measured as percentage overlap with SFARI Gene and ranging from 15.15% to 100%. We conclude that gene panels marketed for use in autism are currently of limited clinical utility, and that sequencing with greater coverage may be more appropriate.

Improved diagnostic yield of neuromuscular disorders applying clinical exome sequencing in patients arising from a consanguineous population

2016 ◽  
Vol 91 (3) ◽  
pp. 386-402 ◽  
Author(s):  
Z. Fattahi ◽  
Z. Kalhor ◽  
M. Fadaee ◽  
R. Vazehan ◽  
E. Parsimehr ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Diagnostic Yield ◽  
Neuromuscular Disorders ◽  
Clinical Exome Sequencing

scholarly journals Comparison of the diagnostic yield of aCGH and genome-wide sequencing across different neurodevelopmental disorders

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Francisco Martinez-Granero ◽  
Fiona Blanco-Kelly ◽  
Carolina Sanchez-Jimeno ◽  
Almudena Avila-Fernandez ◽  
Ana Arteche ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Neurodevelopmental Disorders ◽  
Diagnostic Yield ◽  
Genetic Diagnosis ◽  
Diagnostic Algorithm ◽  
Signs And Symptoms ◽  
Autism Spectrum ◽  
Global Developmental Delay ◽  
Comparative Genomic ◽  
Clinical Exome Sequencing

AbstractMost consensus recommendations for the genetic diagnosis of neurodevelopmental disorders (NDDs) do not include the use of next generation sequencing (NGS) and are still based on chromosomal microarrays, such as comparative genomic hybridization array (aCGH). This study compares the diagnostic yield obtained by aCGH and clinical exome sequencing in NDD globally and its spectrum of disorders. To that end, 1412 patients clinically diagnosed with NDDs and studied with aCGH were classified into phenotype categories: global developmental delay/intellectual disability (GDD/ID); autism spectrum disorder (ASD); and other NDDs. These categories were further subclassified based on the most frequent accompanying signs and symptoms into isolated forms, forms with epilepsy; forms with micro/macrocephaly and syndromic forms. Two hundred and forty-five patients of the 1412 were subjected to clinical exome sequencing. Diagnostic yield of aCGH and clinical exome sequencing, expressed as the number of solved cases, was compared for each phenotype category and subcategory. Clinical exome sequencing was superior than aCGH for all cases except for isolated ASD, with no additional cases solved by NGS. Globally, clinical exome sequencing solved 20% of cases (versus 5.7% by aCGH) and the diagnostic yield was highest for all forms of GDD/ID and lowest for Other NDDs (7.1% versus 1.4% by aCGH) and ASD (6.1% versus 3% by aCGH). In the majority of cases, diagnostic yield was higher in the phenotype subcategories than in the mother category. These results suggest that NGS could be used as a first-tier test in the diagnostic algorithm of all NDDs followed by aCGH when necessary.

scholarly journals Targeted Gene Panel Sequencing for Molecular Diagnosis of Kallmann Syndrome and Normosmic Idiopathic Hypogonadotropic Hypogonadism

2018 ◽  
Vol 127 (08) ◽  
pp. 538-544 ◽  
Author(s):  
Ja Hye Kim ◽  
Go Hun Seo ◽  
Gu-Hwan Kim ◽  
Juyoung Huh ◽  
Il Tae Hwang ◽  
...  
Keyword(s):  
Massively Parallel Sequencing ◽  
Diagnostic Yield ◽  
Hypogonadotropic Hypogonadism ◽  
Cost Effective ◽  
Kallmann Syndrome ◽  
Gene Panel ◽  
Sequence Variants ◽  
Idiopathic Hypogonadotropic Hypogonadism ◽  
Gene Panel Sequencing ◽  
Panel Sequencing

Abstract Background Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is classified either as Kallmann syndrome (KS) with anosmia or normosmic idiopathic hypogonadotropic hypogonadism (nIHH) and caused by mutations in more than 30 different genes. Recent advances in next-generation sequencing technologies have revolutionized the identification of causative genes by using massively parallel sequencing of multiple samples. This study was performed to establish the genetic etiology of IGD using a targeted gene panel sequencing of 69 known human IGD genes. Methods This study included 28 patients with IGD from 27 independent families. Exomes were captured using customized SureSelect kit (Agilent Technologies) and sequenced on the Miseq platform (Illumina, Inc.), which includes a 163,269 bp region spanning 69 genes. Results Four pathogenic and six likely pathogenic sequence variants were identified in 11 patients from 10 of the 27 families (37%) included in the study. We identified two known pathogenic mutations in CHD7 and PROKR2 from two male patients (7.4%). Novel sequence variants were also identified in 10 probands (37%) in CHD7, SOX3, ANOS1, FGFR1, and TACR3. Of these, while eight variants (29.6%) were presumed to be pathogenic or likely pathogenic, the remaining two were classified as variants of uncertain significance. Of the two pre-pubertal males with anosmia, one harbored a novel heterozygous splice site variant in FGFR1. Conclusions The overall diagnostic yield was 37% of the patients who had undergone targeted gene panel sequencing. This approach enables rapid, cost-effective, and comprehensive genetic screening in patients with KS and nIHH.

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