{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T02:20:19Z","timestamp":1784859619653,"version":"3.55.0"},"reference-count":24,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T00:00:00Z","timestamp":1762732800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Loma Linda University School of Medicine","award":["PPM#1001276"],"award-info":[{"award-number":["PPM#1001276"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Mullegama\u2013Klein\u2013Martinez syndrome (MKMS; OMIM #301022) is an X-linked cohesinopathy caused by pathogenic variants in STAG2, which encodes a subunit of the cohesin complex responsible for chromosomal segregation and transcriptional regulation. Individuals typically present with developmental delay, microcephaly, dysmorphic features, and variable congenital anomalies, though complex cardiac malformations are uncommon. Case Presentation: We report a female infant presenting on the first day of life with complex congenital heart disease, including pulmonary atresia, double-outlet right ventricle, large subaortic ventricular septal defect, and patent ductus arteriosus. She exhibited intrauterine growth restriction, mild craniofacial dysmorphism, and left upper-extremity hypotonia. Stepwise genetic evaluation revealed a de novo likely pathogenic STAG2 frameshift variant, c.2972_2975dup (p.His992Glnfs*11), identified by rapid trio whole-exome sequencing. This variant truncates the C-terminal domain critical for cohesin binding. A 3D structural model generated by SWISS-MODEL demonstrated disruption of \u03b2-strand and loop conformations within this domain, consistent with loss of cohesin complex stability. Conclusions: This case expands the phenotypic spectrum of STAG2-related MKM and highlights the role of STAG2 in cardiac development. Recognition of such presentations supports the inclusion of STAG2 in the differential diagnosis for complex congenital heart disease and underscores the diagnostic utility of rapid trio exome sequencing in neonatal care. The utility of 3D protein modeling to illustrate structural consequences of truncating variants provides valuable insight into variant pathogenicity and supports precision diagnosis in cohesinopathies.<\/jats:p>","DOI":"10.3390\/genes16111364","type":"journal-article","created":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T13:51:08Z","timestamp":1762782668000},"page":"1364","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A Novel STAG2 Frameshift Variant in Mullegama\u2013Klein\u2013Martinez Syndrome with Complex Conotruncal Heart Defect"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0203-5261","authenticated-orcid":false,"given":"Hua","family":"Wang","sequence":"first","affiliation":[{"name":"Division of Genetics, Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1002\/ajmg.a.38207","article-title":"De novo loss-of-function variants in STAG2 are associated with developmental delay, microcephaly, and congenital anomalies","volume":"173","author":"Mullegama","year":"2017","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1038\/s41436-018-0085-6","article-title":"Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies","volume":"21","author":"Yuan","year":"2019","journal-title":"Genet. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2828","DOI":"10.1080\/15384101.2019.1658476","article-title":"The expanding phenotypes of cohesinopathies: One ring to rule them all!","volume":"18","author":"Andelfinger","year":"2019","journal-title":"Cell Cycle"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Ros-Pardo, D., G\u00f3mez-Puertas, P., and Marcos-Alcalde, \u00cd. (2024). STAG2: Computational Analysis of Missense Variants Involved in Disease. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25021280"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2113","DOI":"10.1002\/ajmg.a.63247","article-title":"Genomic analyses in Cornelia de Lange Syndrome and related diagnoses: Novel candidate genes, genotype-phenotype correlations and common mechanisms","volume":"191","author":"Kaur","year":"2023","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1002\/dvdy.24510","article-title":"How many roads lead to cohesinopathies?","volume":"246","author":"Banerji","year":"2017","journal-title":"Dev. Dyn."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1136\/jmedgenet-2016-104468","article-title":"STAG1 mutations cause a novel cohesinopathy characterised by unspecific syndromic intellectual disability","volume":"54","author":"Lehalle","year":"2017","journal-title":"J. Med. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Schmidt, J., Dreha-Kulaczewski, S., Zafeiriou, M.P., Schreiber, M.K., Wilken, B., Funke, R., Neuhofer, C.M., Altm\u00fcller, J., Thiele, H., and N\u00fcrnberg, P. (2022). Somatic mosaicism in STAG2-associated cohesinopathies: Expansion of the genotypic and phenotypic spectrum. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.1025332"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Di Muro, E., Palumbo, P., Benvenuto, M., Accadia, M., Di Giacomo, M.C., Manieri, S., Abate, R., Tagliente, M., Castellana, S., and Mazza, T. (2021). Novel STAG1 Frameshift Mutation in a Patient Affected by a Syndromic Form of Neurodevelopmental Disorder. Genes, 12.","DOI":"10.3390\/genes12081116"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e2420343122","DOI":"10.1073\/pnas.2420343122","article-title":"Genomic analysis of 11,555 probands identifies 60 dominant congenital heart disease genes","volume":"122","author":"Sierant","year":"2025","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1136\/heartjnl-2023-323126","article-title":"Genetic syndromes associated with congenital heart disease","volume":"110","author":"Duarte","year":"2024","journal-title":"Heart"},{"key":"ref_12","first-page":"7005","article-title":"A neural crest origin for cohesinopathy heart defects","volume":"24","author":"Schuster","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"101949","DOI":"10.1016\/j.gde.2022.101949","article-title":"Molecular genetic mechanisms of congenital heart disease","volume":"75","author":"Choudhury","year":"2022","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1038\/ng.3627","article-title":"Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing","volume":"48","author":"Sifrim","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1038\/ng.3970","article-title":"Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands","volume":"49","author":"Jin","year":"2017","journal-title":"Nat. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Tan, M., Wang, X., Liu, H., Peng, X., Yang, Y., Yu, H., Xu, L., Li, J., and Cao, H. (2022). Genetic Diagnostic Yield and Novel Causal Genes of Congenital Heart Disease. Front. Genet., 13.","DOI":"10.3389\/fgene.2022.941364"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Provenzano, A., La Barbera, A., Lai, F., Perra, A., Farina, A., Cariati, E., Zuffardi, O., and Giglio, S. (2022). Non-Invasive Detection of a De Novo Frameshift Variant of STAG2 in a Female Fetus: Escape Genes Influence the Manifestation of X-Linked Diseases in Females. J. Clin. Med., 11.","DOI":"10.3390\/jcm11144182"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"105024","DOI":"10.1016\/j.ejmg.2025.105024","article-title":"Novel STAG2 variant expands Mullegama-Klein-Martinez Syndrome phenotype","volume":"76","author":"Duff","year":"2025","journal-title":"Eur. J. Med. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1101\/gr.253211.119","article-title":"Redundant and specific roles of cohesin STAG subunits in chromatin looping and transcriptional control","volume":"30","author":"Casa","year":"2020","journal-title":"Genome Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.gde.2020.02.024","article-title":"Specialized functions of cohesins STAG1 and STAG2 in 3D genome architecture","volume":"61","author":"Cuadrado","year":"2020","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1016\/j.tcb.2023.03.006","article-title":"NIPBL and cohesin: New take on a classic tale","volume":"33","author":"Losada","year":"2023","journal-title":"Trends Cell Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1007\/978-3-031-44087-8_6","article-title":"Neural Crest","volume":"1441","author":"Thattaliyath","year":"2024","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.semcdb.2006.12.004","article-title":"Model systems for the study of heart development and disease. Cardiac neural crest and conotruncal malformations","volume":"18","author":"Hutson","year":"2007","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/s41439-021-00169-3","article-title":"Expanding the known phenotype of Mullegama-Klein-Martinez syndrome in male patients","volume":"8","author":"Freyberger","year":"2021","journal-title":"Hum. 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