<i>GABRA1</i>
            and
            <i>STXBP1</i>
            : Novel genetic causes of Dravet syndrome

Carvill, Gemma L.; Weckhuysen, Sarah; McMahon, Jacinta M.; Hartmann, Corinna; Møller, Rikke S.; Hjalgrim, Helle; Cook, Joseph; Geraghty, Eileen; O’Roak, Brian J.; Petrou, Steven; Clarke, Alison L.; Gill, Deepak; Sadleir, Lynette G.; Muhle, Hiltrud; Spiczak, Sarah von; Nikanorova, Marina; Hodgson, Bree; Gazina, Elena V.; Suls, Arvid; Shendure, Jay; Dibbens, Leanne M.; Jonghe, Peter De; Helbig, Ingo; Berkovic, Samuel F.; Scheffer, Ingrid E.; Mefford, Heather C

doi:10.1212/wnl.0000000000000291

Cited by 243 publications

(246 citation statements)

References 39 publications

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“…For those patients with SCN1A-negative Dravet syndrome, a mutation can sometimes be found in other epilepsy genes including SCN1B, GABRA1, STXBP1, and SCN8A. [32][33][34] In a patient with a newly identified SCN1A variant, it is not always easy to determine whether this genetic abnormality is the cause of the epilepsy syndrome. If the variant is inherited from an unaffected parent and/or is not predicted to affect the protein, it is unlikely to be related to the illness, and this was the case in one of our patients.…”

Section: Discussionmentioning

confidence: 99%

Incidence of Dravet Syndrome in a US Population

et al. 2015

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OBJECTIVE: De novo mutations of the gene sodium channel 1α (SCN1A) are the major cause of Dravet syndrome, an infantile epileptic encephalopathy. US incidence of DS has been estimated at 1 in 40 000, but no US epidemiologic studies have been performed since the advent of genetic testing. METHODS: In a retrospective, population-based cohort of all infants born at Kaiser Permanente Northern California during 2007–2010, we electronically identified patients who received ≥2 seizure diagnoses before age 12 months and who were also prescribed anticonvulsants at 24 months. A child neurologist reviewed records to identify infants who met 4 of 5 criteria for clinical Dravet syndrome: normal development before seizure onset; ≥2 seizures before age 12 months; myoclonic, hemiclonic, or generalized tonic-clonic seizures; ≥2 seizures lasting >10 minutes; and refractory seizures after age 2 years. SCN1A gene sequencing was performed as part of routine clinical care. RESULTS: Eight infants met the study criteria for clinical Dravet syndrome, yielding an incidence of 1 per 15 700. Six of these infants (incidence of 1 per 20 900) had a de novo SCN1A missense mutation that is likely to be pathogenic. One infant had an inherited SCN1A variant that is unlikely to be pathogenic. All 8 experienced febrile seizures, and 6 had prolonged seizures lasting >10 minutes by age 1 year. CONCLUSIONS: Dravet syndrome due to an SCN1A mutation is twice as common in the United States as previously thought. Genetic testing should be considered in children with ≥2 prolonged febrile seizures by 1 year of age.

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Section: Discussionmentioning

confidence: 99%

Incidence of Dravet Syndrome in a US Population

et al. 2015

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“…Accession number for SCN1A : RefSeq NM_001165963.1, NP_001159435.1. Seven patients have previously been reported.aThese eight patients are part of the EuroEPINOMICS‐RES cohort.bLemke et al., 2012.cBayat et al., 2015.dCarvill et al., 2014.eGaily et al., 2013.fBased on the SCN1A database (http://www.gzneurosci.com/scn1adatabase/index.php) and the published papers mentioned in this manuscript.…”

Section: Resultsmentioning

confidence: 99%

“…Seven patients have previously been reported.aLemke et al., 2012.bBayat et al., 2015.cCarvill et al., 2014.dGaily et al., 2013.…”

Section: Resultsmentioning

confidence: 99%

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Pitfalls in genetic testing: the story of missed SCN1A mutations

Djémié

Weckhuysen

Spiczak

et al. 2016

Molec Gen & Gen Med

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BackgroundSanger sequencing, still the standard technique for genetic testing in most diagnostic laboratories and until recently widely used in research, is gradually being complemented by next‐generation sequencing (NGS). No single mutation detection technique is however perfect in identifying all mutations. Therefore, we wondered to what extent inconsistencies between Sanger sequencing and NGS affect the molecular diagnosis of patients. Since mutations in SCN1A, the major gene implicated in epilepsy, are found in the majority of Dravet syndrome (DS) patients, we focused on missed SCN1A mutations.MethodsWe sent out a survey to 16 genetic centers performing SCN1A testing.ResultsWe collected data on 28 mutations initially missed using Sanger sequencing. All patients were falsely reported as SCN1A mutation‐negative, both due to technical limitations and human errors.ConclusionWe illustrate the pitfalls of Sanger sequencing and most importantly provide evidence that SCN1A mutations are an even more frequent cause of DS than already anticipated.

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“…The pathogenicity of SCN1A mutations will have its effect on the wider disease phenotype. Whole exome sequencing in SCN1A negative patients with Dravet syndrome identified GABRA1 and STXBP1making a significant contribution to Dravet syndrome [5].…”

mentioning

confidence: 99%

Dravet Syndrome

Rizk¹

2014

JNSK

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GABRA1 and STXBP1 : Novel genetic causes of Dravet syndrome

Cited by 243 publications

References 39 publications

Incidence of Dravet Syndrome in a US Population

Incidence of Dravet Syndrome in a US Population

Pitfalls in genetic testing: the story of missed SCN1A mutations

Dravet Syndrome

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