@article {Mirabello417, author = {Lisa Mirabello and Payal P Khincha and Steven R Ellis and Neelam Giri and Seth Brodie and Settara C Chandrasekharappa and Frank X Donovan and Weiyin Zhou and Belynda D Hicks and Joseph F Boland and Meredith Yeager and Kristine Jones and Bin Zhu and Mingyi Wang and Blanche P Alter and Sharon A Savage}, title = {Novel and known ribosomal causes of Diamond-Blackfan anaemia identified through comprehensive genomic characterisation}, volume = {54}, number = {6}, pages = {417--425}, year = {2017}, doi = {10.1136/jmedgenet-2016-104346}, publisher = {BMJ Publishing Group Ltd}, 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.}, issn = {0022-2593}, URL = {https://jmg.bmj.com/content/54/6/417}, eprint = {https://jmg.bmj.com/content/54/6/417.full.pdf}, journal = {Journal of Medical Genetics} }