2. Academic Validation
  3. Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency

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

  • Blood. 2021 Jan 28;137(4):493-499. doi: 10.1182/blood.2020006441.
Francesco Saettini 1,  Cecilia Poli 2 3,  Jaime Vengoechea 4 5,  Sonia Bonanomi 1,  Julio C Orellana 6,  Grazia Fazio 7,  Fred H Rodriguez 8 9,  Loreani P Noguera 3,  Claire Booth 10,  Valentina Jarur-Chamy 3,  Marissa Shams 5,  Maria Iascone 11,  Maja Vukic 12,  Serena Gasperini 13,  Manuel Quadri 7,  Amairelys Barroeta Seijas 10,  Elizabeth Rivers 10,  Mario Mauri 14,  Raffaele Badolato 15,  Gianni Cazzaniga 7 14,  Cristina Bugarin 7,  Giuseppe Gaipa 7,  Wilma G M Kroes 16,  Daniele Moratto 17,  Monique M van Oostaijen-Ten Dam 18,  Frank Baas 16,  Silvère van der Maarel 12,  Rocco Piazza 14,  Zeynep H Coban-Akdemir 19 20,  James R Lupski 19 21,  Bo Yuan 19 20,  Ivan K Chinn 2 22,  Lucia Daxinger 12,  Andrea Biondi 1 7
Affiliations

Affiliations

  • 1 Pediatric Hematology Department, Fondazione Monza e Brianza per il Bambino e la sua Mamma (MBBM), University of Milano Bicocca, Monza, Italy.
  • 2 Department of Pediatrics, Baylor College of Medicine, Houston, TX.
  • 3 Facultad de Medicina Clínica Alemana de Santiago, Universidad del Desarrollo, Santiago, Chile.
  • 4 Department of Human Genetics, Emory University, Atlanta, GA.
  • 5 Department of Medicine, Emory University, Atlanta, GA.
  • 6 Division Alergia e Inmunología Clínica, Hospital de Niños de la Santísima Trinidad, Córdoba, Argentina.
  • 7 Centro Ricerca Tettamanti, University of Milano Bicocca, Monza, Italy.
  • 8 Section of Cardiology, Department of Medicine, and.
  • 9 Section of Cardiology, Department of Pediatrics, Emory University, Atlanta, GA.
  • 10 Molecular and Cellular Immunology Section, UCL Institute of Child Health, London, United Kingdom.
  • 11 Molecular Genetics Laboratory, Università Settore Scientifico-Disciplinare Laboratorio di Genetica Medica (USSD LGM), Papa Giovanni XXIII Hospital, Bergamo, Italy.
  • 12 Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
  • 13 Metabolic Rare Disease Unit, Pediatric Department, Fondazione MBBM, University of Milano Bicocca, Monza, Italy.
  • 14 Department of Medicine and Surgery, University of Milano Bicocca-San Gerardo Hospital, Monza, Italy.
  • 15 Pediatrics Clinic and Institute of Molecular Medicine A. Novicelli, Department of Clinical and Experimental Sciences, University of Brescia, ASST Spedali Civili of Brescia, Brescia, Italy.
  • 16 Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
  • 17 Flow Cytometry Laboratory, Diagnostic Department, ASST Spedali Civili di Brescia, Brescia, Italy.
  • 18 Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.
  • 19 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
  • 20 Baylor Genetics Laboratory, Houston, TX.
  • 21 Baylor-Hopkins Center for Mendelian Genomics, Houston, TX; and.
  • 22 Section of Immunology, Allergy, and Rheumatology, Texas Children's Hospital, Houston, TX.
PMID: 32905580 DOI: 10.1182/blood.2020006441
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 compound-heterozygous 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 Fnip1-/- 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.

Figures