Integration of biological/pathophysiological contexts to help clarify genotype-phenotype mismatches in monogenetic diseases. Childhood epilepsies associated with SCN2A as a case study

• Published in: Biochemical pharmacology 2018-05, Vol.151, p.252-262
• Main Authors: Winquist, Raymond J., Cohen, Charles J.
• Format: Article
• Language: English
• Subjects: Epilepsy; Genetic Association Studies; Genotype; Genotype-phenotype; Humans; Ion channels; Monogenetic; Mutation; Mutation, Missense; Nav1.2; NAV1.2 Voltage-Gated Sodium Channel - genetics; Phenotype; Severity of Illness Index; Spasms, Infantile - etiology; Spasms, Infantile - genetics
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2018.01.003

[Display omitted] Monogenetic diseases offer clear human validation for launching drug discovery programs in Pharma designed to develop important new medicines for unmet medical needs. However, mismatches in the genotype-phenotype of presenting patients complicate both the preclinical ‘research target profile’ and the clinical development strategy. Additional biological and pathophysiological data associated with the identified mutations are necessary for more optimal prosecution of these drug discovery programs. This added contextual setting goes beyond identification of modifier genes and needs to encompass microenvironmental factors which can differentially affect the phenotype of patients harboring the same mutation. The Early Infantile Epileptic Encephalopathies (EIEEs) associated with de novo mutations in voltage gated sodium channels are interesting case studies that include examples of genotype-phenotype mismatches. With EIEE11, associated with mutations in SCN2A, incorporation of biological/pathophysiological contexts are helpful in clarifying the apparent genotype-phenotype mismatches which are captured with more reductionist approaches.