Germline mosaicism of a missense variant in KCNC2 in a multiplex family with autism and epilepsy characterized by long‐read sequencing

Autor: Elvisa Mehinovic, Teddi Gray, Meghan Campbell, Jenny Ekholm, Aaron Wenger, William Rowell, Ari Grudo, Jane Grimwood, Jonas Korlach, Christina Gurnett, John N. Constantino, Tychele N. Turner
Rok vydání: 2022
Předmět:
Zdroj: American Journal of Medical Genetics Part A. 188:2071-2081
ISSN: 1552-4833
1552-4825
DOI: 10.1002/ajmg.a.62743
Popis: Currently, protein-coding de novo variants and large copy number variants have been identified as important for ~30% of individuals with autism. One approach to identify relevant variation in individuals who lack these types of events is by utilizing newer genomic technologies. In this study, highly accurate PacBio HiFi long-read sequencing was applied to a family with autism, epileptic encephalopathy, cognitive impairment, and mild dysmorphic features (two affected female siblings, unaffected parents, and one unaffected male sibling) with no known clinical variant. From our long-read sequencing data, a de novo missense variant in the KCNC2 gene (encodes Kv3.2) was identified in both affected children. This variant was phased to the paternal chromosome of origin and is likely a germline mosaic. In silico assessment revealed the variant was not in controls, highly conserved, and predicted damaging. This specific missense variant (Val473Ala) has been shown in both an ortholog and paralog of Kv3.2 to accelerate current decay, shift the voltage dependence of activation, and prevent the channel from entering a long-lasting open state. Seven additional missense variants have been identified in other individuals with neurodevelopmental disorders (p = 1.03 × 10
Databáze: OpenAIRE
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