title: Novel and known ribosomal causes of Diamond-Blackfan anaemia identified through comprehensive genomic characterisation.
abstract: 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 (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.
  
  
  
  Our analyses uncovered heterozygous pathogenic variants in two previously undescribed genes in two families. One family had a non-synonymous variant (p.K77N) inRPL35; the second family had a non-synonymous variant (p. L51S) inRPL18. 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.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Mirabello
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Payal P
authors.initials: PP
authors.lastname: Khincha
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, Kentucky, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Ellis
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Neelam
authors.initials: N
authors.lastname: Giri
authors.affiliation: Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Seth
authors.initials: S
authors.lastname: Brodie
authors.affiliation: Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, Bethesda, Maryland, USA.
authors.forename: Settara C
authors.initials: SC
authors.lastname: Chandrasekharappa
authors.affiliation: Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, Bethesda, Maryland, USA.
authors.forename: Frank X
authors.initials: FX
authors.lastname: Donovan
authors.affiliation: Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Weiyin
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.|Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Belynda D
authors.initials: BD
authors.lastname: Hicks
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.|Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Boland
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.|Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.affiliation: Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Kristine
authors.initials: K
authors.lastname: Jones
authors.affiliation: Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhu
authors.affiliation: Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Mingyi
authors.initials: M
authors.lastname: Wang
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Blanche P
authors.initials: BP
authors.lastname: Alter
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Savage
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D029503:Anemia, Diamond-Blackfan / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D023281:Genomics / Q000379:methods; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D012269:Ribosomal Proteins / Q000235:genetics; D012270:Ribosomes / Q000235:genetics*; D055815:Young Adult
chemical_list: D012269:Ribosomal Proteins
keywords: Diamond-Blackfan anemia; RPL18; RPL35; genetics; ribosome; whole exome sequencing