Describe a case of neuromyelitis-optica-spectrum-disorder (NMOSD) with neutropenia and multiple infections ultimately leading to a diagnosis of common variable immunodeficiency (CVID). We emphasize the importance of obtaining a comprehensive evaluation of the immune system, and also the significance of frequently querying for possible relevant family history. 

Genetic panel testing in Autoimmune-Neurology-Clinics is increasingly available and has potential utility in patients with strong family histories of immunologic disorders or phenotypes suggestive of genetic causes.

A 27-year-old-female delivered her first-child and within four-weeks developed left optic neuritis with visual acuity at worst of 20/150. She was diagnosed with aquaporin-4 (AQP-4) IgG positive NMOSD and started on Rituximab. Within 3-years, she began experiencing frequent infections, and was admitted to the hospital for neutropenia with an immunoglobulin-G level of 468 mg/dL (nl 700-1600). She was evaluated by Immunology for possible CVID and subsequently started on intravenous immune globulin with good response. Family history revealed that her father carries a diagnosis of Waldenström macroglobulinemia and hypogammaglobulinemia.  Both underwent genetic testing and were found to have a shared frameshift variant of uncertain significance (VUS) in the VAV1 gene, with existing literature suggesting that the disease mechanism is via haploinsufficiency.  

Incompletely characterized VUS found in genetic panels presents an increasingly common challenge to clinicians interpreting these test results as well as patients.  VUS in the VAV1 gene resulting in a frameshift is predicted to impact T and B cell development. However, barring costly functional studies or additional genetic testing in relatives, identified VUS does not provide actionable information in terms of family planning. While this case highlights the importance of detailed family history of both neurologic/non-neurologic immune-related disorders and accompanying immunologic evaluation, the identification of VUS in genetic panels and their significance when found in association with rare neurologic diseases continue to present clinical challenges.