Identification of a Shared CD3D Variant Among a Severe Combined Immunodeficiency Cohort of Cabo Verdean Ancestry

Identifying patient populations with recurring and potentially targetable genetic variants is crucial to develop innovative therapeutics such as gene editing. However, many patient populations remain underrepresented in genetic databases, highlighting an unmet need in diagnosis and treatment of immunodeficiency. Cabo Verde is an island country off the coast of West Africa that was uninhabited until the 15^th century, now with a unique genetic admixture of Portuguese and sub-Saharan African descent. Despite a sizable population (500,000 citizens and a global diaspora of nearly 1 million), genomic data from Cabo Verdeans remains limited and genetic conditions among Cabo Verdean patients under investigated. Our institution has now diagnosed and treated 3 non-consanguineous patients of Cabo Verdean ancestry with T^-B⁺NK⁺ severe combined immunodeficiency (SCID) secondary to the homozygous variant CD3D: c.279C>A (p.Cys93*). This variant results in a premature stop codon, with associated loss of CD3δ protein and absent T cell development. All three infants were diagnosed by newborn screening and received busulfan-based conditioning prior to successful hematopoietic cell transplant (HCT). Patient 1 was a male with family history notable for two older siblings who were not assessed by newborn screening but died of pneumonia at 4 months of age. He received a matched unrelated donor transplant at 2 months of age, with transplant course complicated by acute respiratory distress syndrome (ARDS) requiring mechanical ventilation and transverse myelitis at 2 years of age. By 9 months post-HCT, he was off exogenous immune suppression with full donor chimerism and T cell and B cell reconstitution. Patient 2 was a female who was a first cousin once removed of patient 1. She received a haploidentical T cell–depleted graft from her mother at 18 weeks of age. Her HCT course was complicated by polymicrobial sepsis requiring intensive care unit (ICU) admission and EBV viremia requiring rituximab therapy. By one year post-HCT, she had stably discontinued exogenous immune suppression with full donor chimerism, T cell reconstitution, and recovering B cell reconstitution post-rituximab. Patient 3 was a female without family history of immunodeficiency, severe infections, or early infant death, nor a relation to patient 1 or 2. She received a matched unrelated donor HCT at 12 weeks of age, complicated by EBV viremia (requiring rituximab), veno-occlusive disease (VOD), transplant-associated thrombotic microangiopathy (TA-TMA), and cutaneous graft-versus-host disease (GvHD). By one year post-HCT, she was off exogenous immune suppression with full donor chimerism, full T cell reconstitution, and recovering B cell reconstitution post-rituximab. These cases signal the possibility of a CD3D founder variant among Cabo Verdean populations, for which further prevalence studies are warranted. If increased allele frequency is found, it would be appropriate to evaluate gene editing approaches as a potential alternative to stem cell transplant, especially for this SCID variant believed to require more intensive conditioning relative to other forms of SCID.