TY - JOUR T1 - Novel and known ribosomal causes of Diamond-Blackfan anaemia identified through comprehensive genomic characterisation JF - Journal of Medical Genetics JO - J Med Genet DO - 10.1136/jmedgenet-2016-104346 SP - jmedgenet-2016-104346 AU - Lisa Mirabello AU - Payal P Khincha AU - Steven R Ellis AU - Neelam Giri AU - Seth Brodie AU - Settara C Chandrasekharappa AU - Frank X Donovan AU - Weiyin Zhou AU - Belynda D Hicks AU - Joseph F Boland AU - Meredith Yeager AU - Kristine Jones AU - Bin Zhu AU - Mingyi Wang AU - Blanche P Alter AU - Sharon A Savage Y1 - 2017/03/09 UR - http://jmg.bmj.com/content/early/2017/03/09/jmedgenet-2016-104346.abstract N2 - 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. ER -