Exploring the Genotype-Phenotype Correlations in a Child with Inherited Seizure and Thrombocytopenia by Digenic...

Understanding the correlation between genotype and phenotype remains challenging for modern genetics. Digenic network analysis may provide useful models for understanding complex phenotypes that traditional Mendelian monogenic models cannot explain. Clinical data, whole exome sequencing data, in silico, and machine learning analysis were combined to construct a digenic network that may help unveil the complex genotype-phenotype correlations in a child presenting with inherited seizures and thrombocytopenia. The proband inherited a maternal heterozygous missense variant in SCN1A (NM_001165963.4:c.2722G>A) and a paternal heterozygous missense variant in MYH9 (NM_002473.6:c.3323A>C). In silico analysis showed that these two variants may be pathogenic for inherited seizures and thrombocytopenia in the proband. Moreover, focusing on 230 epilepsy-associated genes and 35 thrombopoiesis genes, variant call format data of the proband were analyzed using machine learning tools (VarCoPP 2.0) and Digenic Effect predictor. A digenic network was constructed, and SCN1A and MYH9 were found to be core genes in the network. Further analysis showed that MYH9 might be a modifier of SCN1A, and the variant in MYH9 might not only influence the severity of SCN1A-related seizure but also lead to thrombocytopenia in the bone marrow. In addition, another eight variants might also be co-factors that account for the proband's complex phenotypes. Our data show that as a supplement to the traditional Mendelian monogenic model, digenic network analysis may provide reasonable models for the explanation of complex genotype-phenotype correlations.