The Diverse Genomic Landscape of Diamond–Blackfan Anemia: Two Novel Variants and a Mini-Review

Author:

Pelagiadis Iordanis1ORCID,Kyriakidis Ioannis1ORCID,Katzilakis Nikolaos1ORCID,Kosmeri Chrysoula2ORCID,Veltra Danai3ORCID,Sofocleous Christalena3ORCID,Glentis Stavros4ORCID,Kattamis Antonis4ORCID,Makis Alexandros2ORCID,Stiakaki Eftichia1ORCID

Affiliation:

1. Department of Pediatric Hematology-Oncology, University Hospital of Heraklion, School of Medicine, University of Crete, 71003 Heraklion, Greece

2. Department of Pediatrics, University Hospital of Ioannina, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece

3. Laboratory of Medical Genetics, “Aghia Sophia” Children’s Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece

4. Division of Pediatric Hematology-Oncology, First Department of Pediatrics, “Aghia Sofia” Children’s Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece

Abstract

Diamond–Blackfan anemia (DBA) is a ribosomopathy characterized by bone marrow erythroid hypoplasia, which typically presents with severe anemia within the first months of life. DBA is typically attributed to a heterozygous mutation in a ribosomal protein (RP) gene along with a defect in the ribosomal RNA (rRNA) maturation or levels. Besides classic DBA, DBA-like disease has been described with variations in 16 genes (primarily in GATA1, followed by ADA2 alias CECR1, HEATR3, and TSR2). To date, more than a thousand variants have been reported in RP genes. Splice variants represent 6% of identifiable genetic defects in DBA, while their prevalence is 14.3% when focusing on pathogenic and likely pathogenic (P/LP) variants, thus highlighting the impact of such alterations in RP translation and, subsequently, in ribosome levels. We hereby present two cases with novel pathogenic splice variants in RPS17 and RPS26. Associations of DBA-related variants with specific phenotypic features and malignancies and the molecular consequences of pathogenic variations for each DBA-related gene are discussed. The determinants of the spontaneous remission, cancer development, variable expression of the same variants between families, and selectivity of RP defects towards the erythroid lineage remain to be elucidated.

Publisher

MDPI AG

Subject

Pediatrics, Perinatology and Child Health

Reference48 articles.

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