Whole-genome sequencing offers additional but limited clinical utility compared with reanalysis of whole-exome sequencing

Alfares, Ahmed; Aloraini, Taghrid; subaie, Lamia Al; AlIssa, Abdulelah; Qudsi, Ahmed Al; Alahmad, Ahmed; Mutairi, Fuad Al; Alswaid, Abdulrahman; Alothaim, Ali; Eyaid, Wafaa; Albalwi, Mohammed; Al-Turki, Saeed; Alfadhel, Majid

doi:10.1038/gim.2018.41

Cited by 120 publications

(86 citation statements)

References 21 publications

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“…Of note, 11 cases classified as nondiagnostic in this study were ultimately clinically diagnosed with multiple system atrophy, cerebellar type, and another case was identified with a VUS associated with increased risk for this condition (Gilman et al, 2008;Zhao et al, 2016). We also reclassified variants from our previously reported 76 cases (Fogel et al, 2014) based on current annotation, which has been shown to improve diagnosis over time (Alfares et al, 2018;Ewans et al, 2018;Fogel, 2018b This recessive disorder was diagnosed clinically due to its distinctive phenotype, a second pathogenic variant is presumed to be noncoding.…”

Section: Discussionmentioning

confidence: 97%

“…Of note, 11 cases classified as nondiagnostic in this study were ultimately clinically diagnosed with multiple system atrophy, cerebellar type, and another case was identified with a VUS associated with increased risk for this condition (Gilman et al, ; Zhao et al, ). We also reclassified variants from our previously reported 76 cases (Fogel et al, ) based on current annotation, which has been shown to improve diagnosis over time (Alfares et al, ; Ewans et al, ; Fogel, ; Fogel, Lee, Strom, Deignan, & Nelson, ; Fogel et al, ; Nambot et al, ; Rexach et al, ; Wright et al, ). This resulted in four cases previously classified as nondiagnostic or having a reportable VUS being reclassified with a pathogenic/likely pathogenic genetic variant.…”

Section: Discussionmentioning

confidence: 99%

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A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders

et al. 2019

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Genetic ataxias are associated with mutations in hundreds of genes with high phenotypic overlap complicating the clinical diagnosis. Whole-exome sequencing (WES) has increased the overall diagnostic rate considerably. However, the upper limit of this method remains ill-defined, hindering efforts to address the remaining diagnostic gap. To further assess the role of rare coding variation in ataxic disorders, we reanalyzed our previously published exome cohort of 76 predominantly adult and sporadic-onset patients, expanded the total number of cases to 260, and introduced analyses for copy number variation and repeat expansion in a representative subset.For new cases (n = 184), our resulting clinically relevant detection rate remained *Kathie J. Ngo and Jessica E. Rexach contributed equally to this work. ORCIDJennifer E. Posey http://orcid.org/0000-0003-4814-6765 James R. Lupski http://orcid.org/0000-0001-9907-9246 Brent L. Fogel http://orcid.org/0000-0001-9831-1576 SUPPORTING INFORMATION Additional supporting information may be found online in the Supporting Information section. How to cite this article: Ngo KJ, Rexach JE, Lee H, et al. A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders. Human Mutation. 2020; 41:487-501. https://doi.

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Section: Discussionmentioning

confidence: 97%

“…Of note, 11 cases classified as nondiagnostic in this study were ultimately clinically diagnosed with multiple system atrophy, cerebellar type, and another case was identified with a VUS associated with increased risk for this condition (Gilman et al, ; Zhao et al, ). We also reclassified variants from our previously reported 76 cases (Fogel et al, ) based on current annotation, which has been shown to improve diagnosis over time (Alfares et al, ; Ewans et al, ; Fogel, ; Fogel, Lee, Strom, Deignan, & Nelson, ; Fogel et al, ; Nambot et al, ; Rexach et al, ; Wright et al, ). This resulted in four cases previously classified as nondiagnostic or having a reportable VUS being reclassified with a pathogenic/likely pathogenic genetic variant.…”

Section: Discussionmentioning

confidence: 99%

A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders

et al. 2019

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“…However, it is likely that CES will never reach 100% diagnostic rate even in patients with a clearly genetic etiology because of technical limitations. Despite the encouraging early results from WGS in these “negative” cases, the full potential of WGS in patients who could not be diagnosed by CES remains to be seen (Alfares et al, ). Testing other tissue sources as well as additional modalities at the RNA, epigenetic, and multilocus levels will likely be necessary to resolve an even higher proportion of cases.…”

Section: Discussionmentioning

confidence: 99%

Clinical exome sequencing in 509 Middle Eastern families with suspected Mendelian diseases: The Qatari experience

Al-Dewik

Mohd

Al‐Mureikhi

et al. 2019

American J of Med Genetics Pt A

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BackgroundClinical exome sequencing (CES) is rapidly becoming the diagnostic test of choice in patients with suspected Mendelian diseases especially those that are heterogeneous in etiology and clinical presentation. Reporting large CES series can inform guidelines on best practices for test utilization, and improves accuracy of variant interpretation through clinically‐oriented data sharing.MethodsThis is a retrospective series of 509 probands from Qatar who underwent singleton or trio CES either as a reflex or naïve (first‐tier) test from April 2014 to December 2016 for various clinical indications.ResultsThe CES diagnostic yield for the overall cohort was 48.3% (n = 246). Dual molecular diagnoses were observed in 2.1% of cases; nearly all of whom (91%) were consanguineous. We report compelling variants in 11 genes with no established Mendelian phenotypes. Unlike reflex‐WES, naïve WES was associated with a significantly shorter diagnostic time (3 months vs. 18 months, p < 0.0001).ConclusionMiddle Eastern patients tend to have a higher yield from CES than outbred populations, which has important implications in test choice especially early in the diagnostic process. The relatively high diagnostic rate is likely related to the predominance of recessive diagnoses (60%) since consanguinity and positive family history were strong predictors of a positive CES.

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“…As the cerebellar findings were unique to WBS patient cohort and since the parents were consanguineous, we looked for the possibility of another gene to explain this radiological finding. Further review of the WES data revealed a likely pathogenic homozygous variant (NM_138395.3:c.1595C>G, p.(Ala532Gly)) in MARS2 gene (MIM# 609728), associated with cerebellar atrophy [Thiffault et al, 2006; Alfares et al, 2018]. The variant was absent from gnomAD and our internal control database but presented in his sibling who also had cerebellar atrophy on brain imaging and heterozygote for the familial DDX11 variant.…”

Section: Discussionmentioning

confidence: 99%

Warsaw breakage syndrome: Further clinical and genetic delineation

Alkhunaizi

Shaheen

Bharti

et al. 2018

American J of Med Genetics Pt A

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Warsaw breakage syndrome (WBS) is a recently recognized DDX11-related rare cohesinopathy, characterized by severe prenatal and postnatal growth restriction, microcephaly, developmental delay, cochlear anomalies, and sensorineural hearing loss. Only seven cases have been reported in the English literature, and thus the information on the phenotype and genotype of this interesting condition is limited. We provide clinical and molecular information on five additional unrelated patients carrying novel bi-allelic variants in the DDX11 gene, identified via whole exome sequencing. One of the variants was found to be a novel Saudi founder variant. All identified variants were classified as pathogenic or likely pathogenic except for one that was initially classified as a variant of unknown significance (VOUS) (p.Arg378Pro). Functional characterization of this VOUS using heterologous expression of wild type and mutant DDX11 revealed a marked effect on protein stability, thus confirming pathogenicity of this variant. The phenotypic data of the seven WBS reported patients were compared to our patients for further phenotypic delineation. Although all the reported patients had cochlear hypoplasia, one patient also had posterior labyrinthine anomaly. We conclude that while the cardinal clinical features in WBS (microcephaly, growth retardation, and cochlear anomalies) are almost universally present, the breakage phenotype is highly variable and can be absent in some cases. This report further expands the knowledge of the phenotypic and molecular features of WBS.

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Whole-genome sequencing offers additional but limited clinical utility compared with reanalysis of whole-exome sequencing

Cited by 120 publications

References 21 publications

A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders

A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders

Clinical exome sequencing in 509 Middle Eastern families with suspected Mendelian diseases: The Qatari experience

Warsaw breakage syndrome: Further clinical and genetic delineation

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