Whole‐exome sequencing improves the diagnosis yield in sporadic infantile spasm syndrome

Dimassi, Sarra; Labreuche, Julien; Ville, Dorothée; Calender, Alain; Mignot, Cyril; Boutry‐Kryza, Nadia; Bellescize, Julitta de; Rivier-Ringenbach, Clothilde; Bourel-Ponchel, Emilie; Cheillan, David; Simonet, Thomas; Maincent, Kim; Rossi, Massimiliano; Till, Marianne; Mougou-Zerelli, Soumaya; Edery, Patrick; Saâd, Ali; Héron, Delphine; Portes, Vincent Des; Sanlaville, Damien; Lesca, Gaëtan

doi:10.1111/cge.12636

Cited by 73 publications

(73 citation statements)

References 23 publications

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“…None of the other potentially pathogenic variants found by WES were shared by all four affected individuals. In addition, none of the variants of potential interest identified by WES that were common to the four family members with PPR (4,13,20,21) were found in the remaining family members with PPR (10, 11, 14, 15, and 23) by Sanger sequencing. Further details are in the Supplementary Table S2.…”

Section: Resultsmentioning

confidence: 97%

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Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy

et al. 2016

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Genetic generalized epilepsy (GGE), formerly known as idiopathic generalized epilepsy, is the most common form of epilepsy and is thought to have predominant genetic etiology. GGE are clinically characterized by absence, myoclonic, or generalized tonic-clonic seizures with electroencephalographic pattern of bilateral, synchronous, and symmetrical spike-and-wave discharges. Despite their strong heritability, the genetic basis of generalized epilepsies remains largely elusive. Nevertheless, recent advances in genetic technology have led to the identification of numerous genes and genomic defects in various types of epilepsies in the past few years. In the present study, we performed whole-exome sequencing in a family with GGE consistent with the diagnosis of eyelid myoclonia with absences. We found a nonsense variant (c.196C4T/p.(Arg66*)) in RORB, which encodes the beta retinoid-related orphan nuclear receptor (RORβ), in four affected family members. In addition, two de novo variants (c.218T4C/p.(Leu73Pro); c.1249_1251delACG/p.(Thr417del)) were identified in sporadic patients by trio-based exome sequencing. We also found two de novo deletions in patients with behavioral and cognitive impairment and epilepsy: a 52-kb microdeletion involving exons 5-10 of RORB and a larger 9q21-microdeletion. Furthermore, we identified a patient with intellectual disability and a balanced translocation where one breakpoint truncates RORB and refined the phenotype of a recently reported patient with RORB deletion. Our data support the role of RORB gene variants/CNVs in neurodevelopmental disorders including epilepsy, and especially in generalized epilepsies with predominant absence seizures.

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Section: Resultsmentioning

confidence: 97%

“…Image analysis and base calling was performed using Illumina Real Time Analysis pipeline version 1.12.4.2 with default settings. 12,13 Both sporadic patients with de novo mutations were sequenced as previously described. 14 …”

Section: Whole-exome Sequencingmentioning

confidence: 99%

Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy

et al. 2016

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“…8,9,23 Data from small cohorts of patients with severe epilepsies also highlight the utility of DES for improving molecular diagnoses. [24][25][26] However, these studies rely on data from small, highly selected patient cohorts and may not reflect the diagnostic yield in an unselected sample of patients with epilepsy.…”

Section: Introductionmentioning

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

306

247

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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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“…Since then, reports of exome and genome sequencing analysis for diagnosis (82) and/or genedisease relationships (7,10,44,45,66,94,116) in particular disease cohorts have proliferated in the literature (30,34,36,49,69,108,118,121,124,135). Research groups and clinical laboratories have rapidly implemented exome sequencing, and within the past few years, results from several cohorts have begun to demonstrate the full potential of this technique as a diagnostic tool in the clinic across a broad range of phenotypes (39,68,99,120,133,134,136).…”

Section: What Is the Current Diagnostic Yield For Exome And Genome Sementioning

confidence: 99%

Defining the Clinical Value of a Genomic Diagnosis in the Era of Next-Generation Sequencing

Strande

Berg

2016

Annu. Rev. Genom. Hum. Genet.

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As with all fields of medicine, the first step toward medical management of genetic disorders is obtaining an accurate diagnosis, which often requires testing at the molecular level. Unfortunately, given the large number of genetic conditions without a specific intervention, only rarely does a genetic diagnosis alter patient management-which raises the question, what is the added value of obtaining a molecular diagnosis? Given the fast-paced advancement of genomic technologies, this is an important question to address in the context of genome-scale testing. Here, we address the value of establishing a diagnosis using genome-scale testing and highlight the benefits and drawbacks of such testing. We also review and compare recent major studies implementing genome-scale sequencing methods to identify a molecular diagnosis in cohorts manifesting a broad range of Mendelian monogenic disorders. Finally, we discuss potential future applications of genomic sequencing, such as screening for rare conditions.

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Whole‐exome sequencing improves the diagnosis yield in sporadic infantile spasm syndrome

Cited by 73 publications

References 23 publications

Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy

Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy

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

Defining the Clinical Value of a Genomic Diagnosis in the Era of Next-Generation Sequencing

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