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 417
OP 425
DO 10.1136/jmedgenet-2016-104346
VO 54
IS 6
A1 Mirabello, Lisa
A1 Khincha, Payal P
A1 Ellis, Steven R
A1 Giri, Neelam
A1 Brodie, Seth
A1 Chandrasekharappa, Settara C
A1 Donovan, Frank X
A1 Zhou, Weiyin
A1 Hicks, Belynda D
A1 Boland, Joseph F
A1 Yeager, Meredith
A1 Jones, Kristine
A1 Zhu, Bin
A1 Wang, Mingyi
A1 Alter, Blanche P
A1 Savage, Sharon A
YR 2017
UL http://jmg.bmj.com/content/54/6/417.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 (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.