Whole-exome sequencing reanalysis at 12 months boosts diagnosis and is cost-effective when applied early in Mendelian disorders

Ewans, Lisa; Schofield, Deborah; Shrestha, Rupendra; Zhu, Ying; Gayevskiy, Velimir; Ying, Kevin; Walsh, Corrina; Lee, Eric; Kirk, Edwin P.; Colley, Alison; Ellaway, Carolyn; Turner, Anne; Mowat, David; Worgan, Lisa; Freckmann, Mary‐Louise; Lipke, Michelle; Sachdev, Rani; Miller, David T.; Field, Michael; Dinger, Marcel E.; Buckley, Michael F.; Cowley, Mark J.; Roscioli, Tony

doi:10.1038/gim.2018.39

Cited by 160 publications

(164 citation statements)

References 38 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, ; 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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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: 99%

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

et al. 2019

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“…Studies have shown that WES‐based techniques are new diagnostic strategies for early detection of Mendelian disorders (Ewans et al, ). Our cohort included 40 Chinese nonconsanguineous families with recurrent fetal malformations during the prenatal ultrasound screening.…”

Section: Discussionmentioning

confidence: 99%

Trio‐whole‐exome sequencing and preimplantation genetic diagnosis for unexplained recurrent fetal malformations

et al. 2019

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Whole-exome sequencing (WES) is widely used to detect genetic mutations that cause Mendelian diseases, and has been successfully applied in combination with preimplantation genetic diagnosis (PGD) to avoid the transmission of genetic defects.We investigated 40 nonconsanguineous families with unexplained, recurrent fetal malformations (two or more malformed fetuses) from May 2016 to December 2018.Using Trio-WES, we identified 32 disease-associated variants in 40 families (80% positive rate), which were subsequently verified. Known Mendelian diseases were identified in 12 families (30%), highly suspected Mendelian diseases in 12 families (30%), variants with uncertain significance in 8 families (20%), and no noticeable variants for 8 families (20%). Further analysis showed variants in 22 genes may cause fetal malformations. Four gene variants were detected in fetuses for the first time, which expanded the spectrum of the disease phenotype. Two novel candidate genes may be related to fetal malformations. Of 26 couples receiving PGD on diseaseassociated genes, 3 healthy newborns were delivered, and 4 couples are undergoing pregnancies. We reported the fetal data and developed an optimized genetic testing strategy. Our finding strongly suggests the presence of single gene Mendelian disorders in 60% of those families, and PGD services for couples to have healthy babies.

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“…The two pathogenic findings on CMA (del 1p36 and dup 15q11. [2][3][4][5][6][7][8][9][10][11][12][13] were present in patients with clinical phenotypes consistent with these copy number variants, and these were not detected by research WES analysis.…”

Section: Participants With Concomitant "Positive" Clinical Testingmentioning

confidence: 99%

“…The case above illustrates the importance of revisiting a patient's genetic data over time and illustrates the complex environment of clinical testing, in which not all modalities are available to patients in all settings due to variability in clinical provider awareness, institutional practices, and cost/insurance‐related barriers. With the evolution of genetic testing modalities, continued identification of epilepsy genes, and improved cataloging of knowledge about specific gene variants, a patient whose testing was "negative" years or months ago may have an identifiable genetic etiology upon reanalysis . Given that approximately 70%‐80% of patients with otherwise unexplained epilepsy are thought to have an underlying genetic cause, the genetic evaluation of patients with epilepsy is becoming more routine in clinical practice, particularly with the rationale that identifying genetic causes for epilepsy may guide treatment options for some patients and limit the need for ongoing additional testing.…”

Section: Introductionmentioning

confidence: 99%

Genetic diagnoses in epilepsy: The impact of dynamic exome analysis in a pediatric cohort

et al. 2020

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Objective We evaluated the yield of systematic analysis and/or reanalysis of whole exome sequencing (WES) data from a cohort of well‐phenotyped pediatric patients with epilepsy and suspected but previously undetermined genetic etiology. Methods We identified and phenotyped 125 participants with pediatric epilepsy. Etiology was unexplained at the time of enrollment despite clinical testing, which included chromosomal microarray (57 patients), epilepsy gene panel (n = 48), both (n = 28), or WES (n = 8). Clinical epilepsy diagnoses included developmental and epileptic encephalopathy (DEE), febrile infection‐related epilepsy syndrome, Rasmussen encephalitis, and other focal and generalized epilepsies. We analyzed WES data and compared the yield in participants with and without prior clinical genetic testing. Results Overall, we identified pathogenic or likely pathogenic variants in 40% (50/125) of our study participants. Nine patients with DEE had genetic variants in recently published genes that had not been recognized as epilepsy‐related at the time of clinical testing (FGF12, GABBR1, GABBR2, ITPA, KAT6A, PTPN23, RHOBTB2, SATB2), and eight patients had genetic variants in candidate epilepsy genes (CAMTA1, FAT3, GABRA6, HUWE1, PTCHD1). Ninety participants had concomitant or subsequent clinical genetic testing, which was ultimately explanatory for 26% (23/90). Of the 67 participants whose molecular diagnoses were "unsolved" through clinical genetic testing, we identified pathogenic or likely pathogenic variants in 17 (25%). Significance Our data argue for early consideration of WES with iterative reanalysis for patients with epilepsy, particularly those with DEE or epilepsy with intellectual disability. Rigorous analysis of WES data of well‐phenotyped patients with epilepsy leads to a broader understanding of gene‐specific phenotypic spectra as well as candidate disease gene identification. We illustrate the dynamic nature of genetic diagnosis over time, with analysis and in some cases reanalysis of exome data leading to the identification of disease‐associated variants among participants with previously nondiagnostic results from a variety of clinical testing strategies.

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Whole-exome sequencing reanalysis at 12 months boosts diagnosis and is cost-effective when applied early in Mendelian disorders

Cited by 160 publications

References 38 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

Trio‐whole‐exome sequencing and preimplantation genetic diagnosis for unexplained recurrent fetal malformations

Genetic diagnoses in epilepsy: The impact of dynamic exome analysis in a pediatric cohort

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