Browsing by Author "Mace, Emily"

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    Clinical, immunologic, and genetic characteristics of 148 patients with natural killer cell deficiency
    (2025) Abdalgani, Manar; Hernandez , Evelyn; Pedroza, Luis; Chinn, Ivan; Forbes, Lisa; Rider, Nicholas; Banerjee, Pinaki; Poli Harlowe, María Cecilia; Mahapatra, Sanjana; Canter, Debra; Cao, Tram; Shawver, Linda; Nandiwada, Sarada; Lupski, James; Posey, Jennifer; Ramakrishnan, Rajasekhar; Mace, Emily; Orange, Jordan
    Background: Natural killer (NK) cell deficiency (NKD) is an immunodeficiency phenotype in which abnormality of NK cells is the major clinically relevant immune defect. Objective: We sought to define the clinical, immunologic, and genetic characteristics of patients with NKD to aid in the understanding of these individuals and this cell type and guide future research and clinical practice. Methods: During 2006-2022, 168 individuals with a suspected diagnosis of NKD were enrolled, with comprehensive clinical, immunologic, and genetic data collected and analyzed. Research exome sequencing was performed to identify both known and novel genetic associations. Results: NK cell abnormalities consistent with NKD were confirmed in 148 participants. Most presented during childhood (median age 13 years, range 0-76 years), though 34% were adults. All tested individuals exhibited reduced NK cell cytotoxic function; 44% also had decreased NK cell numbers and/or mature NK cells. Herpesvirus and/or papillomavirus infections were observed in 71%, malignancies were observed in 7%, and a 5% case-fatality rate was noted. Among the 99 participants who underwent research exome sequencing, 29% were considered solved for a likely contributing variant allele, with 52% of these cases involving known genes and 48% involving novel genes. Conclusions: NKD is a phenotypic immunodeficiency associated with increased susceptibility to certain viral infections and cancer with multiple genetic etiologies, revealing key biological pathways for NK cell development and function. This research underscores the role of NK cells in human immune defenses and helps advance the identification of at-risk populations, precise genetic diagnoses, and informed clinical management for patients with NKD.
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    Novel Heterozygous Mutation in NFKB2 Is Associated With Early Onset CVID and a Functional Defect in NK Cells Complicated by Disseminated CMV Infection and Severe Nephrotic Syndrome
    (2019) Aird, Alejandra; Lagos, Macarena; Vargas-Hernández, Alexander; Posey, Jennifer; Coban-Akdemir, Zeynep; Jhangiani, Shalini; Mace, Emily; Reyes, Anaid; King, Alejandra; Cavagnaro, Felipe; Forbes, Lisa; Chinn, Iván; Lupski, James; Orange, Jordan; Poli, Cecilia
    Nuclear factor kappa-B subunit 2 (NF-κB2/p100/p52), encoded by NFKB2 (MIM: 164012) belongs to the NF-κB family of transcription factors that play a critical role in inflammation, immunity, cell proliferation, differentiation and survival. Heterozygous C-terminal mutations in NFKB2 have been associated with early-onset common variable immunodeficiency (CVID), central adrenal insufficiency and ectodermal dysplasia. Only two previously reported cases have documented decreased natural killer (NK) cell cytotoxicity, and little is known about the role of NF-κB2 in NK cell maturation and function. Here we report a 13-year-old female that presented at 6 years of age with a history of early onset recurrent sinopulmonary infections, progressive hair loss, and hypogamaglobulinemia consistent with a clinical diagnosis of CVID. At 9 years of age she had cytomegalovirus (CMV) pneumonia that responded to ganciclovir treatment. Functional NK cell testing demonstrated decreased NK cell cytotoxicity despite normal NK cell numbers, consistent with a greater susceptibility to systemic CMV infection. Research exome sequencing (ES) was performed and revealed a novel de novo heterozygous nonsense mutation in NFKB2 (c.2611C>T, p.Gln871*) that was not carried by either of her parents. The variant was Sanger sequenced and confirmed to be de novo in the patient. At age 12, she presented with a reactivation of the systemic CMV infection that was associated with severe and progressive nephrotic syndrome with histologic evidence of pedicellar effacement and negative immunofluorescence. To our knowledge, this is the third NF-κB2 deficient patient in which an abnormal NK cell function has been observed, suggesting a role for non-canonical NF-κB2 signaling in NK cell cytotoxicity. NK cell function should be assessed in patients with mutations in the non-canonical NF-κB pathway to explore the risk for systemic viral infections that may lead to severe complications and impact patient survival. Similarly NF-κB2 should be considered in patients with combined immunodeficiency who have aberrant NK cell function. Further studies are needed to characterize the role of NF-κB2 in NK cell cytotoxic function.
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    Partial loss-of-function mutations in GINS4 lead to NK cell deficiency with neutropenia
    (2022) Conte, Matilde; Poli, Cecilia; Taglialatela, Angelo; Leuzzi, Giuseppe; Chinn, Ivan; Salinas, Sandra; Rey, Emma; Olivares, Nixa; Veramendi, Liz; Ciccia, Alberto; Lupsk, James; Orange, Jordan; Aldave, Juan; Mace, Emily

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