# A Novel STAG2 Frameshift Variant in Mullegama–Klein–Martinez Syndrome with Complex Conotruncal Heart Defect

## TL;DR

A new STAG2 gene mutation is linked to a rare syndrome with severe heart defects and developmental issues, expanding the known effects of this genetic disorder.

## Contribution

The study reports a novel STAG2 frameshift variant and its structural impact, expanding the clinical and molecular spectrum of Mullegama–Klein–Martinez syndrome.

## Key findings

- A de novo STAG2 frameshift variant (c.2972_2975dup) was identified in a patient with complex heart defects and MKMS.
- 3D modeling showed the variant disrupts the cohesin complex's C-terminal domain structure, likely causing instability.
- The findings highlight the importance of STAG2 in cardiac development and support its inclusion in diagnostic evaluations for congenital heart disease.

## Abstract

Background: Mullegama–Klein–Martinez 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 β-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.