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

  • J Med Genet. 2017 Jun;54(6):417-425. doi: 10.1136/jmedgenet-2016-104346.
Lisa Mirabello  1 ,  Payal P Khincha  1 ,  Steven R Ellis  2 ,  Neelam Giri  1 ,  Seth Brodie  3 ,  Settara C Chandrasekharappa  4 ,  Frank X Donovan  4 ,  Weiyin Zhou  3 ,  Belynda D Hicks  1  3 ,  Joseph F Boland  1  3 ,  Meredith Yeager  1  3 ,  Kristine Jones  3 ,  Bin Zhu  3 ,  Mingyi Wang  3 ,  Blanche P Alter  1 ,  Sharon A Savage  1
Affiliations
  • 1. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
  • 2. Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, Kentucky, USA.
  • 3. Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
  • 4. Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, Bethesda, Maryland, USA.
PMID: 28280134 DOI: 10.1136/jmedgenet-2016-104346
Abstract

Background: 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.

Objectives: We aim to identify the genetic aetiology of DBA.

Methods: Of 87 families with DBA enrolled in an institutional review board-approved cohort study (ClinicalTrials.gov 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.

Results: 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.

Conclusions: 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.

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