A Novel De Novo STAG1 Variant at the RAD21 Binding Interface Is Associated With Hypoglycemia, Recurrent Fever, Immunodeficiency and Features of Classical Cohesinopathies.
Hafiz Muhammad Jafar Hussain, Michael Zimmermann, Stephanie L Safgren et al.
✦ AI-curated · Sources linked
Case in brief
A 5-year-old boy had developmental delay and intellectual disability with feeding difficulties, alongside hypoglycemia, recurrent fever, and immunodeficiency. Trio exome sequencing identified a de novo STAG1 missense variant of uncertain significance, NM_005862.3:c.643G>A (p.Val215Ile). The variant lies at the RAD21 interaction interface; molecular dynamics simulations showed conformational changes comparable to those reported for other STAG1 variants considered likely pathogenic. These findings support a potentially deleterious effect, possibly involving disruption of the STAG1–RAD21 interface, but do not establish the variant’s pathogenicity.
What made this case unusual
The presentation combined classical cohesinopathy features with hypoglycemia, recurrent fever, and immunodeficiency; the STAG1 variant of uncertain significance also localized to the RAD21 interaction interface.
Diagnostic / clinical pearl
In a child with cohesinopathy features, trio exome sequencing may identify a de novo STAG1 variant; computational evidence can support a possible functional effect but does not by itself resolve a variant of uncertain significance.
Why it matters
The case adds clinical and molecular observations to the reported STAG1-related cohesinopathy spectrum, including features not described as classical in the abstract.