Dravet Syndrome: The Critical Importance of Early Diagnosis by Genome Sequencing & Variant Identification

Over 80% of DS patients suffer from truncating and missense mutations leading to a loss- of- function via haploinsufficiency, which neither parent has inherited [7]. However, a small subset of cases can be familial, in which one parent is an asymptomatic mosaic carrier of the SCN1A mutation and thus can pass it on to a child without the parent having DS [8]. AlternativelyFurthermore, a parent or family member could rarely carry the same SCN1A mutation and show only a milder epilepsy phenotype by illustrating incomplete penetrance of the mutation & various expressivity [9]. These cases emphasize that DS is a genetic disease resulting from a new mutation, with inherited cases being the exception rather than the rule [10].

Dravet Syndrome (DS), also identified as Severe Myoclonic Epilepsy of Infancy (SMEI), is a critical genetic epilepsy syndrome [1] . It is a rare genetic epilepsy syndrome defined as beginning in the early start of lifespan with the initial symptoms of extended fevered and afebrile seizures [2]. The seizure types may develop with age, and growth-related interruptions become apparent by the second or third year of lifespan [3]. The most known DS symptoms include stagnation or regression of developmental skills, behavioural issues, and speech difficulties [4]. The mortality ratio of DS could improve to 15-20% risk due to seizure-related causes as well as Sudden Expected Death in Epilepsy (SUDEP). This situation highlights the significance of early diagnosis and intervention in treating this condition [5].

The main genetic reason for DS is the monogenic variants in the SCN1A gene encoding the α-subunit of the voltage-gated neuronal Nav 1.1 sodium channel that is critical for regulating brain excitability [6]. 

Early diagnosis of DS is critical for optimal management because initial DS symptoms could resemble more benign seizure disorders, or a spectrum of epilepsy phenotypes ranging from mild familial febrile seizures to severe epileptic encephalopathies [11]; therefore, leveraging phenotypic information to genomic data would result in the most accurate variant identification & interpretation, which are critical to avoid misdiagnosis [12]. 

Advances in genomic technology are playing a pivotal role in improving DS diagnosis and personalized care. With early diagnosis patients with Dravet syndrome experience fewer seizures and the therapy in young age provides vital support for a child’s development. Next-generation sequencing (NGS) methods, including multi-gene epilepsy panels or whole-genome sequencing, have increased the detection ratio of SCN1A mutations in patients with unexplained early-life seizures [14]. With the help of advanced bioinformatics platforms, like InheriNext®, an accurate variant analysis can offer the sensitivity to detect mosaic mutations at low variant allele frequencies, classify genetic variants efficiently, and translate genetic findings into personalized care plans [15]. For instance, knowing the precise mutation in the SCN1A gene could guide tailored treatment strategies by selecting the effective medications in DS and avoiding those known to trigger seizures, as well as informing prognosis and surveillance by understanding the patient’s SUDEP risk [16].

In the spirit of Dravet Syndrome Awareness Month (June), common practices to conduct genetic NGS testing  combined with  expert variant interpretation exemplifies how far precision medicine has come in providing patients with conditions like DS with the most informed diagnosis and individualized care possible. 

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