Enhanced utility of family-centered diagnostic exome sequencing with inheritance model–based analysis: results from 500 unselected families with undiagnosed genetic conditions

Farwell, Kelly D.; Shahmirzadi, Layla; El-Khechen, Dima; Powis, Zöe; Chao, Elizabeth; Davis, Brigette Tippin; Baxter, Ruth; Zeng, Weizhi; Mroske, Cameron; Parra, Melissa; Gandomi, Stephanie; Lu, Ira; Li, Xiang; Lu, Hong; Lu, Hsiao-Mei; Salvador, David; Ruble, David; Lao, Monica; Fischbach, Soren; Wen, Jennifer X.; Lee, Shela; Elliott, Aaron; Dunlop, Charles; Tang, Sha

doi:10.1038/gim.2014.154

Cited by 414 publications

(455 citation statements)

References 33 publications

(34 reference statements)

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“…Exome library preparation, sequencing, bioinformatics, and data analysis were performed as previously described, the exception being the capture reagent which was IDT xGen Exome Research Panel v1.0 1, 10. Approximately 98% of the patient's and parents' exomes were sequenced at a depth of at least 20X with the mean depth being at least 150X.…”

Section: Methodsmentioning

confidence: 99%

Diagnostic exome sequencing identifies GLI2 haploinsufficiency and chromosome 20 uniparental disomy in a patient with developmental anomalies

Sajan

Powis

Helbig

et al. 2018

Clinical Case Reports

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Section: Methodsmentioning

confidence: 99%

Diagnostic exome sequencing identifies GLI2 haploinsufficiency and chromosome 20 uniparental disomy in a patient with developmental anomalies

Sajan

Powis

Helbig

et al. 2018

Clinical Case Reports

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“…Exome library preparation, sequencing, bioinformatics, and data analysis were performed as previously described. 7 Briefly, samples were prepared using either the SureSelect Target Enrichment System (Agilent Technologies, Santa Clara, CA) 28 or Roche NimbleGen VCRome Exome System (Madison, WI) and sequenced using paired-end, 100-cycle chemistry on the Illumina HiSeq 2000 or 2500 (Illumina, San Diego, CA). Sequence data were aligned to the reference human genome (GRCh37), and variant calls were generated using CASAVA and Pindel.…”

Section: Whole-exome Sequencingmentioning

confidence: 99%

Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy

Helbig

Hagman

Shinde

et al. 2016

Genetics in Medicine

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Purpose:To assess the yield of diagnostic exome sequencing (DES) and to characterize the molecular findings in characterized and novel disease genes in patients with epilepsy. Methods:In an unselected sample of 1,131 patients referred for DES, overall results were compared between patients with and without epilepsy. DES results were examined based on age of onset and epilepsy diagnosis.Results: Positive/likely positive results were identified in 112/293 (38.2%) epilepsy patients compared with 210/732 (28.7%) patients without epilepsy (P = 0.004). The diagnostic yield in characterized disease genes among patients with epilepsy was 33.4% (105/314). KCNQ2, MECP2, FOXG1, IQSEC2, KMT2A, and STXBP1 were most commonly affected by de novo alterations. Patients with epileptic encephalopathies had the highest rate of positive findings (43.4%).A likely positive novel genetic etiology was proposed in 14/200 (7%) patients with epilepsy; this frequency was highest in patients with epileptic encephalopathies (17%). Three genes (COQ4, DNM1, and PURA) were initially reported as likely positive novel disease genes and were subsequently corroborated in independent peer-reviewed publications.Conclusion: DES with analysis and interpretation of both characterized and novel genetic etiologies is a useful diagnostic tool in epilepsy, particularly in severe early-onset epilepsy. The reporting on novel genetic etiologies may further increase the diagnostic yield.

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“…5 Clinical exome sequencing of affected individual 7 and her parents was performed at Ambry Genetics as previously described. 6 All the procedures were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national); proper informed consent was obtained from all guardians.…”

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confidence: 99%

Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood

Edvardson

Nicolae

Agrawal

et al. 2017

The American Journal of Human Genetics

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Enhanced utility of family-centered diagnostic exome sequencing with inheritance model–based analysis: results from 500 unselected families with undiagnosed genetic conditions

Cited by 414 publications

References 33 publications

Diagnostic exome sequencing identifies GLI2 haploinsufficiency and chromosome 20 uniparental disomy in a patient with developmental anomalies

Diagnostic exome sequencing identifies GLI2 haploinsufficiency and chromosome 20 uniparental disomy in a patient with developmental anomalies

Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy

Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood

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