A quantitative definition of the clinical manifestations of GATA2 deficiency in adults
Abstract
Germline GATA2 deficiency is a pleiotropic condition 1-8 characterized by numerous phenotypes, including monocytopenia, immunodeficiency, microbial susceptibilities, and high rates of myeloid malignancies 1,8. Accurate curation of germline GATA2 variants is critical for patient care and requires well-defined phenotypes associated with GATA2 deficiency. The many phenotypes attributed to the condition render a simple description of GATA2 deficiency difficult, complicating the development of GATA2 variant curation rules. Therefore, the Myeloid Malignancy Variant Curation Expert Panel (MM-VCEP) sought to define GATA2 deficiency based on a statistical comparison of phenotype data. To do so, the MM-VCEP systematically analyzed phenotype data and applied statistical comparisons to define the phenotypic features of GATA2 deficiency to inform germline variant curation. The MM-VCEP assembled an international cohort of 339 people with clinically diagnosed GATA2 deficiency from 16 centers in seven countries. The 73 phenotypes of these individuals were compared statistically to those of control participants from the UK Biobank (UKBB). We compared single phenotypes as well as combinations of two, three, and four phenotypes in people with clinically diagnosed GATA2 deficiency to UKBB controls. We defined GATA2 deficiency as any of the 2,903 combinations of two or three phenotypes with log10Odds Ratio ≥3 (OR ≥ 1000). This definition of GATA2 deficiency will inform gene-specific phenotypic criteria used in GATA2 variant curation guidelines that will facilitate standardized variant curation by clinical laboratories worldwide.
Article Details
Authors (47)
Shruthi Mohan
University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
Tilda E Carlelycke
Northwestern University, Chicago, Illinois, United States
Ashwin Lakshman Koppayi
Northwestern University, Chicago, Illinois, United States
Taylor Walker
Northwestern University, Chicago, Illinois, United States
Eran Tallis
University of Rochester Medical Center, Rochester, New York, United States
Amy M. Trottier
Dalhousie University, Halifax, Canada
Katherine R. Calvo
National Institutes of Health Clinical Center, Bethesda, Maryland, United States
Beatriz E. Marciano
National Institutes of Health, Bethesda, Maryland, United States
Amy P. Hsu
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States
Steven M. Holland
Dennis D. Hickstein
National Institutes of Health, Bethesda, Maryland, United States
Marcin W Wlodarski
St. Jude Children Research Hospital, Memphis, Tennessee, United States
Emilia Kozyra
University of Freiburg, Freiburg, Germany
Matthew Collin
Newcastle University, Newcastle Upon Tyne, United Kingdom
Christopher N. Hahn
SA Pathology, Adelaide, Australia
Anna L Brown
SA Pathology, Adelaide, Australia
Piers Blombery
Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
Ing Soo Tiong
Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
Yamuna Kankanige
Peter MacCallum Cancer Centre, Melbourne, Australia
Lucy C Fox
Peter MacCallum Cancer Centre, Melbourne, Australia
Sioban B. Keel
University of Washington, Seattle, Washington, United States
Marshall S. Horwitz
University of Washington, Seattle, Washington, United States
Tom J Vulliamy
Queen Mary University of London, London, United Kingdom
Inderjeet Dokal
Queen Mary University of London, London, United Kingdom
Daniela P Mendes-de-Almeida
Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
Rodrigo Tocantins Calado
Marcela Cavalcante de Andrade Silva
Faculdade de Medicina da Universidade Federal de Alagoas, Maceió, Brazil
Elvira Deolinda Rodrigues Pereira Velloso
Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil
Courtney D DiNardo
The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
Shai Izraeli
Felsenstein Research Institute, Schneider Children's Medical Center of Israel, Tel Aviv University, Petach Tiqva, Israel
Joanne Yacobovich
Schneider Children's Medical Center of Israel, Petach Tikva, Israel
Michaela Sherbeck
Nebraska Cancer Specialists, Omaha, Nebraska, United States
Julia T Warren
Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
Minjie Luo
William J Smith
Wayne State University School of Medicine, Detroit, Michigan, United States
Zachary Hattig
Northwestern University, Chicago, Illinois, United States
Ryan J Stubbins
Leukemia/BMT Program of British Columbia, BC Cancer and Vancouver Coastal Health, Vancouver, British Columbia, Canada
Simone K Feurstein
Heidelberg University Hospital, Heidelberg, Germany
Panagiotis Baliakas
Science for Life Laboratory, Uppsala University, Uppsala, Sweden
Xi Luo
Amagoia Ruiz Martin
Hospital Universitario de Gran Canaria Doctor Negrín, Las Palmas De Gran Canaria, Spain
Adam Gordon
Emery H Bresnick
University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States
Guimin Gao
The University of Chicago, Chicago, Illinois, United States
Masha Kocherginsky
Northwestern University Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, United States
David Wu
Lucy A. Godley