No association between SCN9A and monogenic human epilepsy disorders

Many studies have demonstrated the clinical utility and importance of epilepsy gene panel testing to confirm the specific aetiology of disease, enable appropriate therapeutic interventions, and inform accurate family counselling. Previously, SCN9A gene variants, in particular a c.1921A>T p.(Asn641Tyr) substitution, have been identified as a likely autosomal dominant cause of febrile seizures/febrile seizures plus and other monogenic seizure phenotypes indistinguishable from those associated with SCN1A, leading to inclusion of SCN9A on epilepsy gene testing panels. Here we present serendipitous findings of genetic studies that identify the SCN9A c.1921A>T p.(Asn641Tyr) variant at high frequency in the Amish community in the absence of such seizure phenotypes. Together with findings in UK Biobank these data refute an association of SCN9A with epilepsy, which has important clinical diagnostic implications.

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Identification of a Novel Nonsense Variant in the SCN1A Gene that Causes Febrile Seizure Disorder

Journal of Pediatric Neurology ◽

10.1055/s-0037-1607995 ◽

2017 ◽

Vol 16 (04) ◽

pp. 236-238

Author(s):

Nabila MarchoudI ◽

Abdelfettah Rouissi ◽

Jamal Fekkak ◽

Farah Jouali

Keyword(s):

Febrile Seizure ◽

Febrile Seizures ◽

Seizure Disorder ◽

Gene Encoding ◽

Seizure Disorders ◽

Severe Myoclonic Epilepsy ◽

Epilepsy Gene ◽

Generalized Epilepsy ◽

Febrile Seizures Plus ◽

Scn1a Gene

AbstractThe SCN1A gene, encoding for the voltage-gated sodium channel Nav1.1, is the most clinically relevant epilepsy gene, with most mutations having been documented in a spectrum of epilepsy syndromes, ranging from the relatively benign generalized epilepsy with febrile seizures plus (GEFS+) to severe myoclonic epilepsy in infancy (SMEI), and other rare febrile seizure disorders. To date, more than 1,250 mutations in SCN1A have been linked to epilepsy. In this case, we describe a novel nonsense pathogenic variant (NM_001202435.1; c.327C > G) in SCN1A in a 10-month Moroccan infant with febrile seizure disorder.

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Benefits and safety of multigene panel testing in patients at risk for hereditary breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.28_suppl.16 ◽

2015 ◽

Vol 33 (28_suppl) ◽

pp. 16-16

Author(s):

Nimmi S. Kapoor ◽

Lisa D. Curcio ◽

Carlee A. Blakemore ◽

Amy K. Bremner ◽

Rachel E. McFarland ◽

...

Keyword(s):

Breast Cancer ◽

At Risk ◽

Genetic Testing ◽

Hereditary Breast Cancer ◽

Diagnostic Yield ◽

Gene Panel ◽

Panel Testing ◽

Gene Testing ◽

Gene Panel Testing ◽

Patients At Risk

16 Background: Recently introduced multi-gene panel testing including BRCA1 and BRCA2 genes (BRCA1/2) for hereditary cancer risk has raised concerns with the ability to detect all deleterious BRCA1/2 mutations compared to older methods of sequentially testing BRCA1/2 separately. The purpose of this study is to evaluate rates of pathogenic BRCA1/2mutations and variants of uncertain significance (VUS) between previous restricted algorithms of genetic testing and newer approaches of multi-gene testing. Methods: Data was collected retrospectively from 966 patients who underwent genetic testing at one of three sites from a single institution. Test results were compared between patients who underwent BRCA1/2testing only (limited group, n = 629) to those who underwent multi-gene testing with 5-43 cancer-related genes (panel group, n = 337). Results: Deleterious BRCA1/2 mutations were identified in 37 patients, with equivalent rates between limited and panel groups (4.0% vs 3.6%, respectively, p = 0.86). Thirty-nine patients had a BRCA1/2 VUS, with similar rates between limited and panel groups (4.5% vs 3.3%, respectively, p = 0.49). On multivariate analysis, there was no difference in detection of either BRCA1/2 mutations or VUS between both groups. Of patients undergoing panel testing, an additional 3.9% (n = 13) had non-BRCA pathogenic mutations and 13.4% (n = 45) had non-BRCA VUSs. Mutations in PALB2, CHEK2, and ATM were the most common non-BRCA mutations identified. Conclusions: Multi-gene panel testing detects pathogenic BRCA1/2 mutations at equivalent rates as limited testing and increases the diagnostic yield. Panel testing increases the VUS rate, mainly due to non-BRCA genes. Patients at risk for hereditary breast cancer can safely benefit from upfront, more efficient, multi-gene panel testing.

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