{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:20:07Z","timestamp":1760145607634,"version":"build-2065373602"},"reference-count":45,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2024,7,31]],"date-time":"2024-07-31T00:00:00Z","timestamp":1722384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>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\u2013phenotype 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&gt;A) and a paternal heterozygous missense variant in MYH9 (NM_002473.6:c.3323A&gt;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\u2019s 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\u2013phenotype correlations.<\/jats:p>","DOI":"10.3390\/genes15081004","type":"journal-article","created":{"date-parts":[[2024,7,31]],"date-time":"2024-07-31T17:16:49Z","timestamp":1722446209000},"page":"1004","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Exploring the Genotype\u2013Phenotype Correlations in a Child with Inherited Seizure and Thrombocytopenia by Digenic Network Analysis"],"prefix":"10.3390","volume":"15","author":[{"given":"Shuanglong","family":"Lu","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Tongji Hospital, Tongji University School of Medicine, 389 Xincun Road, Shanghai 200065, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4140-0938","authenticated-orcid":false,"given":"Zhixiao","family":"Niu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Tongji Hospital, Tongji University School of Medicine, 389 Xincun Road, Shanghai 200065, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7774-3900","authenticated-orcid":false,"given":"Xiaohong","family":"Qiao","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Tongji Hospital, Tongji University School of Medicine, 389 Xincun Road, Shanghai 200065, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.ajhg.2015.06.009","article-title":"The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities","volume":"97","author":"Chong","year":"2015","journal-title":"Am. J. Hum. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1056\/NEJMoa1516767","article-title":"Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation","volume":"376","author":"Posey","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e140","DOI":"10.1093\/nar\/gkx557","article-title":"Understanding mutational effects in digenic diseases","volume":"45","author":"Gazzo","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"11878","DOI":"10.1073\/pnas.1815601116","article-title":"Predicting disease-causing variant combinations","volume":"116","author":"Papadimitriou","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1111\/cge.13150","article-title":"Digenic inheritance and genetic modifiers","volume":"93","author":"Deltas","year":"2018","journal-title":"Clin. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1136\/jmedgenet-2013-101713","article-title":"Digenic inheritance in medical genetics","volume":"50","year":"2013","journal-title":"J. Med. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Rahit, K.M.T.H., and Tarailo-Graovac, M. (2020). Genetic Modifiers and Rare Mendelian Disease. Genes, 11.","DOI":"10.3390\/genes11030239"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"R225","DOI":"10.1093\/hmg\/ddh254","article-title":"Mechanisms of non-Mendelian inheritance in genetic disease","volume":"13","author":"Yeyati","year":"2004","journal-title":"Hum. Mol. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1038\/nrg910","article-title":"Beyond Mendel: An evolving view of human genetic disease transmission","volume":"3","author":"Badano","year":"2002","journal-title":"Nat. Rev. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.ajhg.2017.06.004","article-title":"From Peas to Disease: Modifier Genes, Network Resilience, and the Genetics of Health","volume":"101","author":"Riordan","year":"2017","journal-title":"Am. J. Hum. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"S17","DOI":"10.1111\/epi.16386","article-title":"SCN1A-related phenotypes: Epilepsy and beyond","volume":"60","author":"Scheffer","year":"2019","journal-title":"Epilepsia"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.yebeh.2014.11.009","article-title":"A novel inherited SCN1A mutation associated with different neuropsychological phenotypes: Is there a common core deficit?","volume":"43","author":"Passamonti","year":"2015","journal-title":"Epilepsy Behav."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2474","DOI":"10.1111\/j.1528-1167.2010.02790.x","article-title":"Variable epilepsy phenotypes associated with a familial intragenic deletion of the SCN1A gene","volume":"51","author":"Guerrini","year":"2010","journal-title":"Epilepsia"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.gene.2018.04.048","article-title":"MYH9: Structure, functions and role of non-muscle myosin IIA in human disease","volume":"664","author":"Pecci","year":"2018","journal-title":"Gene"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Asensio-Ju\u00e1rez, G., Llorente-Gonz\u00e1lez, C., and Vicente-Manzanares, M. (2020). Linking the Landscape of MYH9-Related Diseases to the Molecular Mechanisms that Control Non-Muscle Myosin II-A Function in Cells. Cells, 9.","DOI":"10.3390\/cells9061458"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1002\/humu.22476","article-title":"MYH9-related disease: A novel prognostic model to predict the clinical evolution of the disease based on genotype-phenotype correlations","volume":"35","author":"Pecci","year":"2014","journal-title":"Hum. Mutat."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1002\/pro.3746","article-title":"VarSite: Disease variants and protein structure","volume":"29","author":"Laskowski","year":"2020","journal-title":"Protein Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"W93","DOI":"10.1093\/nar\/gkz437","article-title":"ORVAL: A novel platform for the prediction and exploration of disease-causing oligogenic variant combinations","volume":"47","author":"Renaux","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3587","DOI":"10.1038\/s41598-024-53494-2","article-title":"Integrative analysis of epilepsy-associated genes reveals expression-phenotype correlations","volume":"14","author":"Chi","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"S11","DOI":"10.5045\/br.2022.2021223","article-title":"Diagnostic workup of inherited platelet disorders","volume":"57","author":"Kim","year":"2022","journal-title":"Blood Res."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Versbraegen, N., Gravel, B., Nachtegael, C., Renaux, A., Verkinderen, E., Now\u00e9, A., Lenaerts, T., and Papadimitriou, S. (2023). Faster and more accurate pathogenic combination predictions with VarCoPP2.0. BMC Bioinform., 24.","DOI":"10.1186\/s12859-023-05291-3"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"101690","DOI":"10.1016\/j.artmed.2019.06.006","article-title":"Using game theory and decision decomposition to effectively discern and characterise bi-locus diseases","volume":"99","author":"Versbraegen","year":"2019","journal-title":"Artif. Intell. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"D900","DOI":"10.1093\/nar\/gkv1068","article-title":"DIDA: A curated and annotated digenic diseases database","volume":"44","author":"Gazzo","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"baac023","DOI":"10.1093\/database\/baac023","article-title":"Scaling up oligogenic diseases research with OLIDA: The Oligogenic Diseases Database","volume":"2022","author":"Nachtegael","year":"2022","journal-title":"Database"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"D638","DOI":"10.1093\/nar\/gkac1000","article-title":"The STRING database in 2023: Protein-protein association networks and functional enrichment analyses for any sequenced genome of interest","volume":"51","author":"Szklarczyk","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"D672","DOI":"10.1093\/nar\/gkad1025","article-title":"The Reactome Pathway Knowledgebase 2024","volume":"52","author":"Milacic","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_28","unstructured":"GTEx Consortium (2013). The Genotype-Tissue Expression (GTEx) project. Nat. Genet., 45, 580\u2013585."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"W556","DOI":"10.1093\/nar\/gkz430","article-title":"GEPIA2: An enhanced web server for large-scale expression profiling and interactive analysis","volume":"47","author":"Tang","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1515\/dx-2020-0149","article-title":"Hickam\u2019s dictum, Occam\u2019s razor, and Crabtree\u2019s bludgeon: A case of renal failure and a clavicular mass","volume":"9","author":"Blaser","year":"2022","journal-title":"Diagnosis"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1097\/MOP.0000000000001072","article-title":"Occam\u2019s razor dulled: The occurrence of multiple genetic diagnoses","volume":"33","author":"Linscott","year":"2021","journal-title":"Curr. Opin. Pediatr."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Spedicati, B., Morgan, A., Pianigiani, G., Musante, L., Rubinato, E., Santin, A., Nardone, G.G., Faletra, F., and Girotto, G. (2022). Challenging Occam\u2019s Razor: Dual Molecular Diagnoses Explain Entangled Clinical Pictures. Genes, 13.","DOI":"10.3390\/genes13112023"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Katsanis, N. (2016). The continuum of causality in human genetic disorders. Genome Biol., 17.","DOI":"10.1186\/s13059-016-1107-9"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Rosina, E., Pezzani, L., Pezzoli, L., Marchetti, D., Bellini, M., Pilotta, A., Calabrese, O., Nicastro, E., Cirillo, F., and Cereda, A. (2022). Atypical, Composite, or Blended Phenotypes: How Different Molecular Mechanisms Could Associate in Double-Diagnosed Patients. Genes, 13.","DOI":"10.3390\/genes13071275"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"100165","DOI":"10.1016\/j.xhgg.2022.100165","article-title":"Toward reporting standards for the pathogenicity of variant combinations involved in multilocus\/oligogenic diseases","volume":"4","author":"Papadimitriou","year":"2023","journal-title":"Hum. Genet. Genom. Adv."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Ameratunga, R., Woon, S.-T., Bryant, V.L., Steele, R., Slade, C., Leung, E.Y., and Lehnert, K. (2017). Clinical Implications of Digenic Inheritance and Epistasis in Primary Immunodeficiency Disorders. Front. Immunol., 8.","DOI":"10.3389\/fimmu.2017.01965"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1212\/WNL.0b013e3181e62088","article-title":"Four generations of epilepsy caused by an inherited microdeletion of the SCN1A gene","volume":"75","author":"Suls","year":"2010","journal-title":"Neurology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1136\/jmg.2009.074328","article-title":"Mechanisms for variable expressivity of inherited SCN1A mutations causing Dravet syndrome","volume":"47","author":"Depienne","year":"2010","journal-title":"J. Med. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e1103","DOI":"10.1002\/mgg3.1103","article-title":"Modifier genes in SCN1A-related epilepsy syndromes","volume":"8","author":"Mulder","year":"2020","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e111","DOI":"10.1111\/epi.13811","article-title":"Cacna1g is a genetic modifier of epilepsy in a mouse model of Dravet syndrome","volume":"58","author":"Calhoun","year":"2017","journal-title":"Epilepsia"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.eplepsyres.2015.11.016","article-title":"Hlf is a genetic modifier of epilepsy caused by voltage-gated sodium channel mutations","volume":"119","author":"Hawkins","year":"2016","journal-title":"Epilepsy Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1744806918788638","DOI":"10.1177\/1744806918788638","article-title":"Nonmuscle myosin II isoforms interact with sodium channel \u03b1 subunits","volume":"14","author":"Dash","year":"2018","journal-title":"Mol. Pain"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"88","DOI":"10.4161\/bioa.29766","article-title":"The role of vertebrate nonmuscle Myosin II in development and human disease","volume":"4","author":"Ma","year":"2014","journal-title":"BioArchitecture"},{"key":"ref_44","first-page":"1495","article-title":"Non-muscle myosin II in disease: Mechanisms and therapeutic opportunities","volume":"8","author":"Horwitz","year":"2015","journal-title":"Dis. Model. Mech."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Javier-Torrent, M., and Saura, C.A. (2020). Conventional and Non-Conventional Roles of Non-Muscle Myosin II-Actin in Neuronal Development and Degeneration. Cells, 9.","DOI":"10.3390\/cells9091926"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/8\/1004\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:27:16Z","timestamp":1760110036000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/8\/1004"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,31]]},"references-count":45,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2024,8]]}},"alternative-id":["genes15081004"],"URL":"https:\/\/doi.org\/10.3390\/genes15081004","relation":{},"ISSN":["2073-4425"],"issn-type":[{"type":"electronic","value":"2073-4425"}],"subject":[],"published":{"date-parts":[[2024,7,31]]}}}