Limitations of exome sequencing in detecting rare and undiagnosed diseases

Burdick, Kendall J.; Cogan, Joy D.; Rives, Lynette; Robertson, Amy K.; Koziura, Mary; Brokamp, Elly; Duncan, Laura; Hannig, Vickie; Pfotenhauer, Jean P.; Vanzo, Rena; Paul, Michael S.; Bican, Anna; Morgan, Thomas M.; Duis, Jessica; Newman, John H.; Hamid, Rizwan; Phillips, John A.

doi:10.1002/ajmg.a.61558

Cited by 73 publications

(64 citation statements)

References 36 publications

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“…When WES returns negative or inconclusive results, for many, the diagnostic odyssey is abandoned or halted. Yet it is clear that re-analysis of WES data can often result in diagnosis in 10–15% of these cases [ 2 ].…”

Section: Discussionmentioning

confidence: 99%

“…Yield is highly influenced by recruitment type (e.g., single proband versus trio), bioinformatic pipelines, study year, consanguinity, case complexity and degree of prior genetic evaluation. Yields tend to increase with study year (due to increasing novel genes, conditions, and technological advances) and in cohorts with a high degree of consanguinity [ 2 ]. Conversely yields are lower in cohorts with highly complex cases necessitating challenging interpretation, e.g.…”

Section: Introductionmentioning

confidence: 99%

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Diagnostic yield of rare skeletal dysplasia conditions in the radiogenomics era

et al. 2021

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Background Skeletal dysplasia (SD) conditions are rare genetic diseases of the skeleton, encompassing a heterogeneous group of over 400 disorders, and represent approximately 5% of all congenital anomalies. Developments in genetic and treatment technologies are leading to unparalleled therapeutic advances; thus, it is more important than ever to molecularly confirm SD conditions. Data on ‘rates-of-molecular yields’ in SD conditions, through exome sequencing approaches, is limited. Figures of 39% and 52.5% have been reported in the USA (n = 54) and South Korea (n = 185) respectively. Methods We discuss a single-centre (in the UK) experience of whole-exome sequencing (WES) in a cohort of 15 paediatric patients (aged 5 months to 12 years) with SD disorders previously molecularly unconfirmed. Our cohort included patients with known clinical diagnoses and undiagnosed skeletal syndromes. Extensive phenotyping and expert radiological review by a panel of international SD radiology experts, coupled with a complex bioinformatics pipeline, allowed for both gene-targeted and gene-agnostic approaches. Results Significant variants leading to a likely or confirmed diagnosis were identified in 53.3% (n = 8/15) of patients; 46.7% (n = 7/15) having a definite molecular diagnosis and 6.7% (n = 1/15) having a likely molecular diagnosis. We discuss this in the context of a rare disease in general and specifically SD presentations. Of patients with known diagnoses pre-WES (n = 10), molecular confirmation occurred in 7/10 cases, as opposed to 1/5 where a diagnosis was unknown pre-test. Thus, diagnostic return is greatest where the diagnosis is known pre-test. For WGS (whole genome sequencing, the next iteration of WES), careful case selection (ideally of known diagnoses pre-test) will yield highest returns. Conclusions Our results highlight the cost-effective use of WES-targeted bioinformatic analysis as a diagnostic tool for SD, particularly patients with presumed SD, where detailed phenotyping is essential. Thorough co-ordinated clinical evaluation between clinical, radiological, and molecular teams is essential for improved yield and clinical care. WES (and WGS) yields will increase with time, allowing faster diagnoses, avoiding needless investigations, ensuring individualised patient care and patient reassurance. Further diagnoses will lead to increased information on natural history/mechanistic details, and likely increased therapies and clinical trials.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Diagnostic yield of rare skeletal dysplasia conditions in the radiogenomics era

et al. 2021

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“…28 If no variants are identi ed through WES, then further testing is needed, though the cost-effectiveness of such studies needs determination. 2 Our results highlight the cost-effective use of WES-targeted bioinformatic analysis as a diagnostic tool for SD, particularly for patients with presumed SD, where detailed phenotyping is essential. The thorough clinical evaluative approach and planning between clinical, radiological, and molecular teams is essential for improved service provision.…”

Section: Resultsmentioning

confidence: 69%

“…Approximately 80% of the 7300 rare diseases have a known genetic cause, and whole-exome sequencing (WES) is commonly the nal diagnostic step in such cases with diagnostic yields averaging around 31% (24-68%). [1][2][3] The broad range in WES diagnostic yields (see Table 1) re ects varying cohorts and clinical indications for testing (i.e. diagnostic rates are higher in selected cohorts with conspicuous phenotypes).…”

Section: Introductionmentioning

confidence: 99%

“…Yields tend to increase with study year (due to increasing novel genes, conditions, and technological advances) and in cohorts with a high degree of consanguinity. 2 Conversely yields are lower in cohorts with highly complex cases necessitating challenging interpretation, e.g. cases where two or three independent genetic diagnoses lead to an aggregate phenotype.…”

Section: Introductionmentioning

confidence: 99%

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Diagnostic Yield of Rare Skeletal Dysplasia Conditions in the Radiogenomics Era – A UK Experience

Sabir

Morley

Sheikh

et al. 2020

Preprint

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BACKGROUNDSkeletal dysplasia (SD) conditions are rare genetic diseases of the skeleton, encompassing a heterogeneous group of over 400 disorders, and represent approximately 5% of all congenital anomalies. Developments in genetic and treatment technologies are leading to unparalleled therapeutic advances; thus, it is more important than ever to molecularly confirm SD conditions. Data on ‘rates-of-molecular yields’ in SD conditions, through exome sequencing approaches, is limited. Figures of 39% and 52.5% have been reported in the USA (n=54) and South Korea (n=185) respectively.We discuss a single-centre UK experience of whole-exome sequencing (WES) in a cohort of 15 paediatric patients (aged 5 months to 12 years) with SD disorders previously molecularly unconfirmed. Our cohort included patients with known clinical diagnoses and undiagnosed skeletal syndromes. Extensive phenotyping and expert radiological review by a panel of international SD radiology experts, coupled with a complex bioinformatics pipeline, allowed for both gene-targeted and gene-agnostic approaches. RESULTSSignificant variants leading to a likely or confirmed diagnosis were identified in 53.3% (n = 8/15) of patients; 46.7% (n= 7/15) having a definite molecular diagnosis and 6.7% (n= 1/15) having a likely molecular diagnosis. We discuss this in the context of a rare disease in general and specifically SD presentations. Of patients with known diagnoses pre-WES (n=10), molecular confirmation occurred in 7/10 cases, as opposed to 1/5 where a diagnosis was unknown pre-test. Thus, diagnostic return is greatest where the diagnosis is known pre-test. For WGS (whole genome sequencing, the next iteration of WES), careful case selection (ideally of known diagnoses pre-test) will yield highest returns.CONCLUSIONSOur results highlight the cost-effective use of WES-targeted bioinformatic analysis as a diagnostic tool for SD, particularly patients with presumed SD, where detailed phenotyping is essential. Thorough co-ordinated clinical evaluation between clinical, radiological, and molecular teams is essential for improved yield and clinical care. WES (and WGS) yields will increase with time, allowing faster diagnoses, avoiding needless investigations, ensuring individualised patient care and patient reassurance. Further diagnoses will lead to increased information on natural history/mechanistic details, and likely increased therapies and clinical trials.

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At-Risk Genomic Findings for Pediatric-Onset Disorders From Genome Sequencing vs Medically Actionable Gene Panel in Proactive Screening of Newborns and Children

et al. 2023

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ImportanceAlthough the clinical utility of genome sequencing for critically ill children is well recognized, its utility for proactive pediatric screening is not well explored.ObjectiveTo evaluate molecular findings from screening ostensibly healthy children with genome sequencing compared with a gene panel for medically actionable pediatric conditions.Design, Setting, and ParticipantsThis case series study was conducted among consecutive, apparently healthy children undergoing proactive genetic screening for pediatric disorders by genome sequencing (n = 562) or an exome-based panel of 268 genes (n = 606) from March 1, 2018, through July 31, 2022.ExposuresGenetic screening for pediatric-onset disorders using genome sequencing or an exome-based panel of 268 genes.Main Outcomes and MeasuresMolecular findings indicative of genetic disease risk.ResultsOf 562 apparently healthy children (286 girls [50.9%]; median age, 29 days [IQR, 9-117 days]) undergoing screening by genome sequencing, 46 (8.2%; 95% CI, 5.9%-10.5%) were found to be at risk for pediatric-onset disease, including 22 children (3.9%) at risk for high-penetrance disorders. Sequence analysis uncovered molecular diagnoses among 32 individuals (5.7%), while copy number variant analysis uncovered molecular diagnoses among 14 individuals (2.5%), including 4 individuals (0.7%) with chromosome scale abnormalities. Overall, there were 47 molecular diagnoses, with 1 individual receiving 2 diagnoses; of the 47 potential diagnoses, 22 (46.8%) were associated with high-penetrance conditions. Pathogenic variants in medically actionable pediatric genes were found in 6 individuals (1.1%), constituting 12.8% (6 of 47) of all diagnoses. At least 1 pharmacogenomic variant was reported for 89.0% (500 of 562) of the cohort. In contrast, of 606 children (293 girls [48.3%]; median age, 26 days [IQR, 10-67 days]) undergoing gene panel screening, only 13 (2.1%; 95% CI, 1.0%-3.3%) resulted in potential childhood-onset diagnoses, a significantly lower rate than those screened by genome sequencing (P &lt; .001).Conclusions and RelevanceIn this case series study, genome sequencing as a proactive screening approach for children, due to its unrestrictive gene content and technical advantages in comparison with an exome-based gene panel for medically actionable childhood conditions, uncovered a wide range of heterogeneous high-penetrance pediatric conditions that could guide early interventions and medical management.

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Limitations of exome sequencing in detecting rare and undiagnosed diseases

Cited by 73 publications

References 36 publications

Diagnostic yield of rare skeletal dysplasia conditions in the radiogenomics era

Diagnostic yield of rare skeletal dysplasia conditions in the radiogenomics era

Diagnostic Yield of Rare Skeletal Dysplasia Conditions in the Radiogenomics Era – A UK Experience

At-Risk Genomic Findings for Pediatric-Onset Disorders From Genome Sequencing vs Medically Actionable Gene Panel in Proactive Screening of Newborns and Children

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