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J Med Genet. 2017 Jun;54(6):417-425. doi: 10.1136/jmedgenet-2016-104346. Epub 2017 Mar 9.

Novel and known ribosomal causes of Diamond-Blackfan anaemia identified through comprehensive genomic characterisation.

Author information

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, Kentucky, USA.
Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, Bethesda, Maryland, USA.



Diamond-Blackfan anaemia (DBA) is an inherited bone marrow failure syndrome (IBMFS) characterised by erythroid hypoplasia. It is associated with congenital anomalies and a high risk of developing specific cancers. DBA is caused predominantly by autosomal dominant pathogenic variants in at least 15 genes affecting ribosomal biogenesis and function. Two X-linked recessive genes have been identified.


We aim to identify the genetic aetiology of DBA.


Of 87 families with DBA enrolled in an institutional review board-approved cohort study ( Identifier:NCT00027274), 61 had genetic testing information available. Thirty-five families did not have a known genetic cause and thus underwent comprehensive genomic evaluation with whole exome sequencing, deletion and CNV analyses to identify their disease-associated pathogenic variant. Controls for functional studies were healthy mutation-negative individuals enrolled in the same study.


Our analyses uncovered heterozygous pathogenic variants in two previously undescribed genes in two families. One family had a non-synonymous variant (p.K77N) in RPL35; the second family had a non-synonymous variant (p. L51S) in RPL18. Both of these variants result in pre-rRNA processing defects. We identified heterozygous pathogenic variants in previously known DBA genes in 16 of 35 families. Seventeen families who underwent genetic analyses are yet to have a genetic cause of disease identified.


Overall, heterozygous pathogenic variants in ribosomal genes were identified in 44 of the 61 families (72%). De novo pathogenic variants were observed in 57% of patients with DBA. Ongoing studies of DBA genomics will be important to understand this complex disorder.


Diamond-Blackfan anemia; RPL18; RPL35; genetics; ribosome; whole exome sequencing

[Indexed for MEDLINE]

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