Comprehensive use of extended exome analysis improves diagnostic yield in rare disease: a retrospective survey in 1,059 cases

Bergant, Gaber; Maver, Aleš; Lovrečić, Luca; Čuturilo, Goran; Hodžić, Alenka; Peterlin, Borut

doi:10.1038/gim.2017.142

Cited by 67 publications

(68 citation statements)

References 14 publications

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“…Therefore, we highly recommended WES in 2018, and more patients underwent WES than Panel (172 vs 34). The positive rate of WES in this study was 36.6% (63/172), which is consistent with our previous study (38.7%, 12/31)29 and a large cohort study that included 1059 patients by Bergant et al (42.2%) 32. Notebaly, 248 pediatric patients underwent NGS during the incorporation time, and 28 patients were excluded.…”

supporting

confidence: 91%

The combination of whole‐exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders

et al. 2019

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This retrospective study aims to investigate the diagnostic yields of multiple strategies of next-generation sequencing (NGS) for children with rare neurological disorders (NDs). A total of 220 pediatric patients with NDs who visited our hospital between Jan 2017 and Dec 2018 and had undergone NGS were included. Most patients were 5 years old or younger, and the number of patients visiting the hospital decreased with age. Seizures were the most common symptom in this cohort. The positive rates for targeted NGS panels (Panel), whole-exome sequencing (WES), and copy number variation sequencing (CNVseq) were 26.5% (9/34), 36.6% (63/172), and 16.7% (22/132), respectively. The positive rate for patients undergoing a combination of WES and CNVseq (WES + CNVseq) was 47.8% (54/113), which was significantly better than the positive rate for patients who underwent WES alone (32.7%, 37/113). A total of 83 variants were found in 42 genes, and SCN1A was the most frequently mutanted gene. Twenty-four CNVs were identified in 22 patients: two CNVs were inherited from the mother; 12 CNVs were de novo; and the CNV origins could not be determined in 10 patients. WES + CNVseq may potentially be the mostly effective NGS approach for diagnosis of rare NDs in pediatric patients. K E Y W O R D Scopy number variation sequencing, diagnostic yield, neurological disorders, targeted nextgeneration sequencing panels, whole-exome sequencing

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confidence: 91%

The combination of whole‐exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders

et al. 2019

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“…Concerning mtDNA analysis, only one study on this topic was published: Bergant et al re‐evaluated a cohort of 1.059 ES cases of which 39% ( n = 413) of cases had a neurological referral indication in the broadest sense in. They diagnosed three additional mtDNA mutations (2× m.3243A>G (60% heteroplasmy), referral indication MELAS; 1× m.14598T>C (22%heteroplasmy) referral indication LHON) hereby increasing the diagnostic yield by 0.3% …”

Section: Discussionmentioning

confidence: 99%

“…They diagnosed three additional mtDNA mutations (2× m.3243A>G (60% heteroplasmy), referral indication MELAS; 1× m.14598T>C (22%heteroplasmy) referral indication LHON) hereby increasing the diagnostic yield by 0.3%. 9 First, we aimed to evaluate the feasibility of analyzing the mtDNA by ES in a diagnostic context. We showed that we were able to increase the overall diagnostic yield in a cohort including non-neurological disease by 1.8% even in a setting where targeted mtDNA analyses were used prior to ES in clinical cases with a high suspicion of a certain pathogenic mtDNA variant (eg, LHON, MELAS).…”

Section: Discussionmentioning

confidence: 99%

“…This method was shown to be feasible when compared to Sanger sequencing in 46 subjects . Recently, a retrospective analysis of 1059 cases referred for exome sequencing revealed three additional diagnoses when mtDNA analysis was added to the diagnostic algorithm …”

Section: Introductionmentioning

confidence: 99%

“…8 Recently, a retrospective analysis of 1059 cases referred for exome sequencing revealed three additional diagnoses when mtDNA analysis was added to the diagnostic algorithm. 9 Here, we evaluate if mtDNA analysis as an additional filter step in the clinical ES evaluation increases the overall diagnostic lead. Furthermore, we evaluate if the quality of mtDNA analysis by ES is comparable to that of targeted mtDNA-NGS with respect to recall rate, precision and heteroplasmy levels.…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial DNA mutation analysis from exome sequencing—A more holistic approach in diagnostics of suspected mitochondrial disease

Wagner

Berutti

Lorenz‐Depiereux

et al. 2019

J of Inher Metab Disea

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Diagnostics for suspected mitochondrial disease (MD) can be challenging and necessitate invasive procedures like muscle biopsy. This is due to the extremely broad genetic and phenotypic spectrum, disease genes on both nuclear and mitochondrial DNA (mtDNA), and the tissue specificity of mtDNA variants. Exome sequencing (ES) has revolutionized the diagnostics for MD. However, the nuclear and mtDNA are investigated with separate tests, increasing costs and duration of diagnostics. The full potential of ES is often not exploited as the additional analysis of “off‐target reads” deriving from the mtDNA can be used to analyze both genomes. We performed mtDNA analysis by ES of 2111 cases in a clinical setting. We further assessed the recall rate and precision as well as the estimation of heteroplasmy by ES data by comparison with targeted mtDNA next generation sequencing in 49 cases. ES identified known pathogenic mtDNA point mutations in 38 individuals, increasing the diagnostic yield by nearly 2%. Analysis of mtDNA variants by ES had a high recall rate (96.2 ± 5.6%) and an excellent precision (99.5 ± 2.2%) when compared to the gold standard of targeted mtDNA next generation sequencing. ES estimated heteroplasmy levels with an average difference of 6.6 ± 3.8%, sufficient for clinical decision making. Taken together, the mtDNA analysis from ES is of sufficient quality for clinical diagnostics. We therefore propose ES, investigating both nuclear and mtDNA, as first line test in individuals with suspected MD. One should be aware, that a negative result does not exclude MD and necessitates further test (in additional tissues).

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The etiology of VACTERL association: Current knowledge and hypotheses

Solomon¹

2018

Am J Med Genet

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VACTERL association is a condition involving the presence of multiple congenital anomalies.The condition was first described more than four decades ago, and is not extremely rare. However, relatively little is understood about the causes and underlying biology of the condition as a whole. There are many reasons for this, but there is increasing recognition that VACTERL is extremely clinically as well as etiologically heterogeneous, and this heterogeneity--as well as other hypothesized factors--have caused challenges to identifying the causes for a substantial proportion of patients. Current knowledge about the causes of this condition (or group of conditions) are described, followed by a discussion of possibilities that may reveal more answers for patients as well as researchers and clinicians who work related to this disorder. K E Y W O R D S

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Comprehensive use of extended exome analysis improves diagnostic yield in rare disease: a retrospective survey in 1,059 cases

Cited by 67 publications

References 14 publications

The combination of whole‐exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders

The combination of whole‐exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders

Mitochondrial DNA mutation analysis from exome sequencing—A more holistic approach in diagnostics of suspected mitochondrial disease

The etiology of VACTERL association: Current knowledge and hypotheses

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