RT Journal Article SR Electronic T1 Novel and known ribosomal causes of Diamond-Blackfan anaemia identified through comprehensive genomic characterisation JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP jmedgenet-2016-104346 DO 10.1136/jmedgenet-2016-104346 A1 Lisa Mirabello A1 Payal P Khincha A1 Steven R Ellis A1 Neelam Giri A1 Seth Brodie A1 Settara C Chandrasekharappa A1 Frank X Donovan A1 Weiyin Zhou A1 Belynda D Hicks A1 Joseph F Boland A1 Meredith Yeager A1 Kristine Jones A1 Bin Zhu A1 Mingyi Wang A1 Blanche P Alter A1 Sharon A Savage YR 2017 UL http://jmg.bmj.com/content/early/2017/03/09/jmedgenet-2016-104346.abstract AB 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 (7 2%). 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.