Abstract
PurposePathogenic variants in SCN2A cause a wide range of neurodevelopmental phenotypes. Reports of genotype–phenotype correlations are often anecdotal, and the available phenotypic data have not been systematically analyzed. MethodsWe extracted phenotypic information from primary descriptions of SCN2A-related disorders in the literature between 2001 and 2019, which we coded in Human Phenotype Ontology (HPO) terms. With higher-level phenotype terms inferred by the HPO structure, we assessed the frequencies of clinical features and investigated the association of these features with variant classes and locations within the NaV1.2 protein. ResultsWe identified 413 unrelated individuals and derived a total of 10,860 HPO terms with 562 unique terms. Protein-truncating variants were associated with autism and behavioral abnormalities. Missense variants were associated with neonatal onset, epileptic spasms, and seizures, regardless of type. Phenotypic similarity was identified in 8/62 recurrent SCN2A variants. Three independent principal components accounted for 33% of the phenotypic variance, allowing for separation of gain-of-function versus loss-of-function variants with good performance. ConclusionOur work shows that translating clinical features into a computable format using a standardized language allows for quantitative phenotype analysis, mapping the phenotypic landscape of SCN2A-related disorders in unprecedented detail and revealing genotype–phenotype correlations along a multidimensional spectrum.
Highlights
Over the last decade, more than 100 genetic etiologies have been identified for neurodevelopmental disorders, which include the developmental and epileptic encephalopathies (DEE)
The DEE are a group of childhood epilepsies associated with multiple neurological and non-neurological comorbidities that frequently start in the first years of life and are associated with drug-resistant epilepsy[1]
We have recently demonstrated that the Human Phenotype Ontology (HPO) framework can determine clinical similarities between individuals for gene discovery[20], identify clinical constellations associated with de novo variants[21], and delineate longitudinal disease phenotypes[22]
Summary
More than 100 genetic etiologies have been identified for neurodevelopmental disorders, which include the developmental and epileptic encephalopathies (DEE). The SCN2A gene encodes the α-subunit of the neuronally expressed type II voltage-gated sodium channel, known as NaV1.26,7 Both gain-of-function (GoF) and loss-of-function (LoF) mechanisms have been implicated as underlying disease mechanisms, in addition to several complex functional alterations that cannot as be categorized[8,9]. The SCN2A gene was identified independently in three distinct phenotypes: benign familial infantile seizures[10,11], autism spectrum disorders (ASD)[12], and DEE13–15. While these conditions still represent the most wellrecognized SCN2A-related phenotypes, many clinical presentations overlap, and others have been suggested[8,16]. It has been hypothesized that early-onset epilepsy phenotypes are mainly associated with GoF variants, while later-onset epilepsy and nonepilepsy phenotypes including autism and intellectual disability are associated with LoF variants[6,17]
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