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Bone Marrow Failure
Genotype-phenotype association and variant characterization in Diamond Blackfan anemia caused by pathogenic variants in RPL35A
Ferrata Storti Foundation
Haematologica 2021 Volume 106(5):1303-1310
D. Matthew Gianferante,1 Marcin W. Wlodarski,2,3 Evangelia Atsidaftos,4
Lydie Da Costa,5,6 Polyxeni Delaporta,7 Jason E. Farrar,8 Frederick D. Goldman,9 Maryam Hussain,4 Antonis Kattamis,7 Thierry Leblanc,5 Jeffrey M. Lipton,4 Charlotte M. Niemeyer,2 Dagmar Pospisilova,10 Paola Quarello,11
Ugo Ramenghi,12 Vijay G. Sankaran,13 Adrianna Vlachos,4 Jana Volejnikova,10 Blanche P. Alter,1 Sharon A. Savage1 and Neelam Giri1
1Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, USA; 2Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany; 3St. Jude Children's Research Hospital, Memphis, TN, USA; 4Feinstein Institutes for Medical Research, Division of Hematology/Oncology and Cellular Therapy, Cohen Children's Medical Center, Northwell Health, New York, NY, USA; 5Service d’Hématologie Biologique, Hôpital Robert-Debré, Université de Paris, Paris, France; 6Laboratory of Excellence for Red Blood Cells, GR-Ex, Paris, France; 7First Department of Pediatrics, National and Kapodistrian University of Athens, Athens, Greece; 8Arkansas Children’s Research Institute and University of Arkansas for Medical Sciences, Little Rock, AR, USA; 9University of Alabama at Birmingham, Birmingham, AL, USA; 10Palacky University and University Hospital, Olomouc, Czech Republic; 11Regina Margherita Children's Hospital, Torino, Italy; 12Pediatric and Public Health Science, University of Torino, Torino, Italy and 13Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
ABSTRACT
Diamond Blackfan anemia (DBA) is predominantly an autosomal dominant inherited red cell aplasia primarily caused by pathogenic germline variants in ribosomal protein genes. DBA due to pathogen- ic RPL35A variants has been associated with large 3q29 deletions and phe- notypes not common in DBA. We conducted a multi-institutional genotype- phenotype study of 45 patients with DBA associated with pathogenic RPL35A germline variants and curated the variant data on 21 additional cases from the literature. Genotype-phenotype analyses were conducted compar- ing patients with large deletions versus all other pathogenic variants in RPL35A. Twenty-two of the 45 cases had large deletions in RPL35A. After adjusting for multiple tests, a statistically significant association was observed between patients with a large deletion and steroid-resistant ane- mia, neutropenia, craniofacial abnormalities, chronic gastrointestinal prob- lems, and intellectual disabilities (P<0.01) compared with all other pathogen- ic variants. Non-large deletion pathogenic variants were spread across RPL35A with no apparent hot spot and 56% of the individual family variants were observed more than once. In this, the largest known study of DBA patients with pathogenic RPL35A variants, we determined that patients with large deletions have a more severe phenotype that is clinically different from those with non-large deletion variants. Genes of interest also deleted in the 3q29 region that could be associated with some of these phenotypic features include LMLN and IQCG. Management of DBA due to large RPL35A dele- tions may be challenging due to complex problems and require comprehen- sive assessments by multiple specialists including immunological, gastroin- testinal, and developmental evaluations to provide optimal multidisciplinary care.
Correspondence:
NEELAM GIRI
girin@mail.nih.gov
Received: January 7, 2020. Accepted: April 1, 2020. Pre-published: April 2, 2020.
https://doi.org/10.3324/haematol.2020.246629
©2021 NIH (National Institutes of Health)
haematologica | 2021; 106(5)
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