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1. Antibody Deficiency in Patients with Biallelic KARS1 Mutations

Author

Saettini, F, Guerra, F, Fazio, G, Bugarin, C, Mcmillan, H, Ohtake, A, Ardissone, A, Itoh, M, Giglio, S, Cappuccio, G, Giardino, G, Romano, R, Quadri, M, Gasperini, S, Moratto, D, Chiarini, M, Akira, I, Fukuhara, Y, Hayakawa, I, Okazaki, Y, Mauri, M, Piazza, R, Cazzaniga, G, Biondi, A, Saettini F., Guerra F., Fazio G., Bugarin C., McMillan H. J., Ohtake A., Ardissone A., Itoh M., Giglio S., Cappuccio G., Giardino G., Romano R., Quadri M., Gasperini S., Moratto D., Chiarini M., Akira I., Fukuhara Y., Hayakawa I., Okazaki Y., Mauri M., Piazza R., Cazzaniga G., Biondi A., Saettini, F, Guerra, F, Fazio, G, Bugarin, C, Mcmillan, H, Ohtake, A, Ardissone, A, Itoh, M, Giglio, S, Cappuccio, G, Giardino, G, Romano, R, Quadri, M, Gasperini, S, Moratto, D, Chiarini, M, Akira, I, Fukuhara, Y, Hayakawa, I, Okazaki, Y, Mauri, M, Piazza, R, Cazzaniga, G, Biondi, A, Saettini F., Guerra F., Fazio G., Bugarin C., McMillan H. J., Ohtake A., Ardissone A., Itoh M., Giglio S., Cappuccio G., Giardino G., Romano R., Quadri M., Gasperini S., Moratto D., Chiarini M., Akira I., Fukuhara Y., Hayakawa I., Okazaki Y., Mauri M., Piazza R., Cazzaniga G., and Biondi A.

Abstract

Biallelic KARS1 mutations cause KARS-related diseases, a rare syndromic condition encompassing central and peripheral nervous system impairment, heart and liver disease, and deafness. KARS1 encodes the t-RNA synthase of lysine, an aminoacyl-tRNA synthetase, involved in different physiological mechanisms (such as angiogenesis, post-translational modifications, translation initiation, autophagy and mitochondrial function). Although patients with immune-hematological abnormalities have been individually described, results have not been collectively discussed and functional studies investigating how KARS1 mutations affect B cells have not been performed. Here, we describe one patient with severe developmental delay, sensoneurinal deafness, acute disseminated encephalomyelitis, hypogammaglobulinemia and recurrent infections. Pathogenic biallelic KARS1 variants (Phe291Val/ Pro499Leu) were associated with impaired B cell metabolism (decreased mitochondrial numbers and activity). All published cases of KARS-related diseases were identified. The corresponding authors and researchers involved in the diagnosis of inborn errors of immunity or genetic syndromes were contacted to obtain up-to-date clinical and immunological information. Seventeen patients with KARS-related diseases were identified. Recurrent/severe infections (9/17) and B cell abnormalities (either B cell lymphopenia [3/9], hypogammaglobulinemia [either IgG, IgA or IgM; 6/15] or impaired vaccine responses [4/7]) were frequently reported. Immunoglobulin replacement therapy was given in five patients. Full immunological assessment is warranted in these patients, who may require detailed investigation and specific supportive treatment.

Published
2023

2. Correction to: Antibody Deficiency in Patients with Biallelic KARS1 Mutations (Journal of Clinical Immunology, (2023), 43, 8, (2115-2125), 10.1007/s10875-023-01584-7)

Author

Saettini F., Saettini, F, Guerra, F, Fazio, G, Bugarin, C, Mcmillan, H, Ohtake, A, Ardissone, A, Itoh, M, Giglio, S, Cappuccio, G, Giardino, G, Romano, R, Quadri, M, Gasperini, S, Moratto, D, Chiarini, M, Ishiguro, A, Fukuhara, Y, Hayakawa, I, Okazaki, Y, Mauri, M, Piazza, R, Cazzaniga, G, Biondi, A, Saettini F., Guerra F., Fazio G., Bugarin C., McMillan H. J., Ohtake A., Ardissone A., Itoh M., Giglio S., Cappuccio G., Giardino G., Romano R., Quadri M., Gasperini S., Moratto D., Chiarini M., Ishiguro A., Fukuhara Y., Hayakawa I., Okazaki Y., Mauri M., Piazza R., Cazzaniga G., Biondi A., Saettini F., Saettini, F, Guerra, F, Fazio, G, Bugarin, C, Mcmillan, H, Ohtake, A, Ardissone, A, Itoh, M, Giglio, S, Cappuccio, G, Giardino, G, Romano, R, Quadri, M, Gasperini, S, Moratto, D, Chiarini, M, Ishiguro, A, Fukuhara, Y, Hayakawa, I, Okazaki, Y, Mauri, M, Piazza, R, Cazzaniga, G, Biondi, A, Saettini F., Guerra F., Fazio G., Bugarin C., McMillan H. J., Ohtake A., Ardissone A., Itoh M., Giglio S., Cappuccio G., Giardino G., Romano R., Quadri M., Gasperini S., Moratto D., Chiarini M., Ishiguro A., Fukuhara Y., Hayakawa I., Okazaki Y., Mauri M., Piazza R., Cazzaniga G., and Biondi A.

Abstract

During the submission of the accepted manuscript, first names and surnames had been inverted. The list of authors has been corrected above. The original version has been corrected.

Published
2023

3. Identical EP300 variant leading to Rubinstein–Taybi syndrome with different clinical and immunologic phenotype

Author

Saettini, F, Fazio, G, Bonati, M, Moratto, D, Massa, V, Di Fede, E, Castiglioni, S, Marchetti, D, Chiarini, M, Sottini, A, Iascone, M, Cazzaniga, G, Imberti, L, Biondi, A, Gervasini, C, Badolato, R, Saettini F., Fazio G., Bonati M. T., Moratto D., Massa V., Di Fede E., Castiglioni S., Marchetti D., Chiarini M., Sottini A., Iascone M., Cazzaniga G., Imberti L., Biondi A., Gervasini C., Badolato R., Saettini, F, Fazio, G, Bonati, M, Moratto, D, Massa, V, Di Fede, E, Castiglioni, S, Marchetti, D, Chiarini, M, Sottini, A, Iascone, M, Cazzaniga, G, Imberti, L, Biondi, A, Gervasini, C, Badolato, R, Saettini F., Fazio G., Bonati M. T., Moratto D., Massa V., Di Fede E., Castiglioni S., Marchetti D., Chiarini M., Sottini A., Iascone M., Cazzaniga G., Imberti L., Biondi A., Gervasini C., and Badolato R.

Abstract

The Rubinstein–Taybi syndrome (RSTS) is a rare developmental disorder characterized by craniofacial dysmorphisms, broad thumbs and toes, intellectual disability, growth deficiency, and recurrent infections. Mutations in the cyclic adenosine monophosphate response element-binding protein (CREB)-binding protein (CREBBP) or in the E1A-associated protein p300 (EP300) genes have been demonstrated in 55% (RSTS1) and up to 8% of the patients (RSTS2), respectively. Dysfunction of immune response has been reported in a subgroup of individuals with RSTS. Here we characterize two patients carrying the same EP300 variant and distinctive RSTS features (including congenital heart abnormalities, short stature, feeding problems, and gastroesophageal reflux). Whole exome sequencing did not support a dual molecular diagnosis hypothesis. Nonetheless, patients showed distinct clinical manifestations and immunological features. The most severe phenotype was associated with reduced T-cell production and diversity. This latter feature was confirmed in a control group of four RSTS patients.

Published
2022

4. When to suspect GATA2 deficiency in pediatric patients: from complete blood count to diagnosis

Author

Saettini, F, Coliva, T, Vendemini, F, Moratto, D, Savoldi, G, Borlenghi, E, Masetti, R, Niemeyer, C, Biondi, A, Balduzzi, A, Bonanomi, S, Saettini F., Coliva T., Vendemini F., Moratto D., Savoldi G., Borlenghi E., Masetti R., Niemeyer C. M., Biondi A., Balduzzi A., Bonanomi S., Saettini, F, Coliva, T, Vendemini, F, Moratto, D, Savoldi, G, Borlenghi, E, Masetti, R, Niemeyer, C, Biondi, A, Balduzzi, A, Bonanomi, S, Saettini F., Coliva T., Vendemini F., Moratto D., Savoldi G., Borlenghi E., Masetti R., Niemeyer C. M., Biondi A., Balduzzi A., and Bonanomi S.

Published
2021

5. Case Report: Hypomorphic Function and Somatic Reversion in DOCK8 Deficiency in One Patient With Two Novel Variants and Sclerosing Cholangitis

Author

Saettini, F, Fazio, G, Moratto, D, Galbiati, M, Zucchini, N, Ippolito, D, Dinelli, M, Imberti, L, Mauri, M, Melzi, M, Bonanomi, S, Gerussi, A, Pinelli, M, Barisani, C, Bugarin, C, Chiarini, M, Giacomelli, M, Piazza, R, Cazzaniga, G, Invernizzi, P, Giliani, S, Badolato, R, Biondi, A, Saettini F., Fazio G., Moratto D., Galbiati M., Zucchini N., Ippolito D., Dinelli M. E., Imberti L., Mauri M., Melzi M. L., Bonanomi S., Gerussi A., Pinelli M., Barisani C., Bugarin C., Chiarini M., Giacomelli M., Piazza R., Cazzaniga G., Invernizzi P., Giliani S. C., Badolato R., Biondi A., Saettini, F, Fazio, G, Moratto, D, Galbiati, M, Zucchini, N, Ippolito, D, Dinelli, M, Imberti, L, Mauri, M, Melzi, M, Bonanomi, S, Gerussi, A, Pinelli, M, Barisani, C, Bugarin, C, Chiarini, M, Giacomelli, M, Piazza, R, Cazzaniga, G, Invernizzi, P, Giliani, S, Badolato, R, Biondi, A, Saettini F., Fazio G., Moratto D., Galbiati M., Zucchini N., Ippolito D., Dinelli M. E., Imberti L., Mauri M., Melzi M. L., Bonanomi S., Gerussi A., Pinelli M., Barisani C., Bugarin C., Chiarini M., Giacomelli M., Piazza R., Cazzaniga G., Invernizzi P., Giliani S. C., Badolato R., and Biondi A.

Abstract

DOCK8 deficiency is a combined immunodeficiency due to biallelic variants in dedicator of cytokinesis 8 (DOCK8) gene. The disease has a wide clinical spectrum encompassing recurrent infections (candidiasis, viral and bacterial infections), virally driven malignancies and immune dysregulatory features, including autoimmune (cytopenia and vasculitis) as well as allergic disorders (eczema, asthma, and food allergy). Hypomorphic function and somatic reversion of DOCK8 has been reported to result in incomplete phenotype without IgE overproduction. Here we describe a case of DOCK8 deficiency in a 8-year-old Caucasian girl. The patient’s disease was initially classified as autoimmune thrombocytopenia, which then evolved toward a combined immunodeficiency phenotype with recurrent infections, persistent EBV infection and lymphoproliferation. Two novel variants (one deletion and one premature stop codon) were characterized, resulting in markedly reduced, but not absent, DOCK8 expression. Somatic reversion of the DOCK8 deletion was identified in T cells. Hypomorphic function and somatic reversion were associated with restricted T cell repertoire, decreased STAT5 phosphorylation and impaired immune synapse functioning in T cells. Although the patient presented with incomplete phenotype (absence of markedly increase IgE and eosinophil count), sclerosing cholangitis was incidentally detected, thus indicating that hypomorphic function and somatic reversion of DOCK8 may delay disease progression but do not necessarily prevent from severe complications.

Published
2021

6. Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency

Author

Saettini, F, Poli, C, Vengoechea, J, Bonanomi, S, Orellana, J, Fazio, G, Rodriguez III, F, Noguera, L, Booth, C, Jarur-Chamy, V, Shams, M, Iascone, M, Vukic, M, Gasperini, S, Quadri, M, Seijas, A, Rivers, E, Mauri, M, Badolato, R, Cazzaniga, G, Bugarin, C, Gaipa, G, Kroes, W, Moratto, D, van Oostaijen-Ten Dam, M, Baas, F, van der Maarel, S, Piazza, R, Coban-Akdemir, Z, Lupski, J, Yuan, B, Chinn, I, Daxinger, L, Biondi, A, Saettini F., Poli C., Vengoechea J., Bonanomi S., Orellana J. C., Fazio G., Rodriguez III F. H., Noguera L. P., Booth C., Jarur-Chamy V., Shams M., Iascone M., Vukic M., Gasperini S., Quadri M., Seijas A. B., Rivers E., Mauri M., Badolato R., Cazzaniga G., Bugarin C., Gaipa G., Kroes W. G. M., Moratto D., van Oostaijen-Ten Dam M. M., Baas F., van der Maarel S., Piazza R., Coban-Akdemir Z. H., Lupski J. R., Yuan B., Chinn I. K., Daxinger L., Biondi A., Saettini, F, Poli, C, Vengoechea, J, Bonanomi, S, Orellana, J, Fazio, G, Rodriguez III, F, Noguera, L, Booth, C, Jarur-Chamy, V, Shams, M, Iascone, M, Vukic, M, Gasperini, S, Quadri, M, Seijas, A, Rivers, E, Mauri, M, Badolato, R, Cazzaniga, G, Bugarin, C, Gaipa, G, Kroes, W, Moratto, D, van Oostaijen-Ten Dam, M, Baas, F, van der Maarel, S, Piazza, R, Coban-Akdemir, Z, Lupski, J, Yuan, B, Chinn, I, Daxinger, L, Biondi, A, Saettini F., Poli C., Vengoechea J., Bonanomi S., Orellana J. C., Fazio G., Rodriguez III F. H., Noguera L. P., Booth C., Jarur-Chamy V., Shams M., Iascone M., Vukic M., Gasperini S., Quadri M., Seijas A. B., Rivers E., Mauri M., Badolato R., Cazzaniga G., Bugarin C., Gaipa G., Kroes W. G. M., Moratto D., van Oostaijen-Ten Dam M. M., Baas F., van der Maarel S., Piazza R., Coban-Akdemir Z. H., Lupski J. R., Yuan B., Chinn I. K., Daxinger L., and Biondi A.

Abstract

Agammaglobulinemia is the most profound primary antibody deficiency that can occur due to an early termination of B-cell development. We here investigated 3 novel patients, including the first known adult, from unrelated families with agammaglobulinemia, recurrent infections, and hypertrophic cardiomyopathy (HCM). Two of them also presented with intermittent or severe chronic neutropenia. We identified homozygous or compoundheterozygous variants in the gene for folliculin interacting protein 1 (FNIP1), leading to loss of the FNIP1 protein. B-cell metabolism, including mitochondrial numbers and activity and phosphatidylinositol 3-kinase/AKT pathway, was impaired. These defects recapitulated the Fnip12/2 animal model. Moreover, we identified either uniparental disomy or copy-number variants (CNVs) in 2 patients, expanding the variant spectrum of this novel inborn error of immunity. The results indicate that FNIP1 deficiency can be caused by complex genetic mechanisms and support the clinical utility of exome sequencing and CNV analysis in patients with broad phenotypes, including agammaglobulinemia and HCM. FNIP1 deficiency is a novel inborn error of immunity characterized by early and severe B-cell development defect, agammaglobulinemia, variable neutropenia, and HCM. Our findings elucidate a functional and relevant role of FNIP1 in B-cell development and metabolism and potentially neutrophil activity.

Published
2021

7. Two siblings presenting with novel ADA2 variants, lymphoproliferation, persistence of large granular lymphocytes, and T-cell perturbations

Author

Saettini, F, Fazio, G, Corti, P, Quadri, M, Bugarin, C, Gaipa, G, Penco, F, Moratto, D, Chiarini, M, Baronio, M, Gazzurelli, L, Imberti, L, Paghera, S, Giliani, S, Cazzaniga, G, Plebani, A, Badolato, R, Lougaris, V, Gattorno, M, Biondi, A, Saettini F., Fazio G., Corti P., Quadri M., Bugarin C., Gaipa G., Penco F., Moratto D., Chiarini M., Baronio M., Gazzurelli L., Imberti L., Paghera S., Giliani S., Cazzaniga G., Plebani A., Badolato R., Lougaris V., Gattorno M., Biondi A., Saettini, F, Fazio, G, Corti, P, Quadri, M, Bugarin, C, Gaipa, G, Penco, F, Moratto, D, Chiarini, M, Baronio, M, Gazzurelli, L, Imberti, L, Paghera, S, Giliani, S, Cazzaniga, G, Plebani, A, Badolato, R, Lougaris, V, Gattorno, M, Biondi, A, Saettini F., Fazio G., Corti P., Quadri M., Bugarin C., Gaipa G., Penco F., Moratto D., Chiarini M., Baronio M., Gazzurelli L., Imberti L., Paghera S., Giliani S., Cazzaniga G., Plebani A., Badolato R., Lougaris V., Gattorno M., and Biondi A.

Abstract

The presence of large granular lymphocytes has been reported in patients with ADA2 deficiency and T-LGL leukemia. Here we describe two siblings with novel ADA2 variants, expanding the mutational spectrum of ADA2 deficiency. We show that lymphoproliferation, persistence of large granular lymphocytes, T-cell perturbations, and activation of PI3K pathway, measured by means of phosphorylation levels of S6, are detectable in DADA2 patients without T-LGL leukemia.

Published
2020

8. A novel EP300 mutation associated with Rubinstein-Taybi syndrome type 2 presenting as combined immunodeficiency

Author

Saettini, F, Moratto, D, Grioni, A, Maitz, S, Iascone, M, Rizzari, C, Pavan, F, Spinelli, M, Bettini, L, Biondi, A, Badolato, R, Saettini, Francesco, Moratto, Daniele, Grioni, Andrea, Maitz, Silvia, Iascone, Maria, Rizzari, Carmelo, Pavan, Fabio, Spinelli, Marco, Bettini, Laura Rachele, Biondi, Andrea, Badolato, Raffaele, Saettini, F, Moratto, D, Grioni, A, Maitz, S, Iascone, M, Rizzari, C, Pavan, F, Spinelli, M, Bettini, L, Biondi, A, Badolato, R, Saettini, Francesco, Moratto, Daniele, Grioni, Andrea, Maitz, Silvia, Iascone, Maria, Rizzari, Carmelo, Pavan, Fabio, Spinelli, Marco, Bettini, Laura Rachele, Biondi, Andrea, and Badolato, Raffaele

Published
2018

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