Novel and known ribosomal causes of Diamond-Blackfan anaemia identified through comprehensive genomic characterisation

作者：Mirabello Lisa; Khincha Payal P; Ellis Steven R; Giri Neelam; Brodie Seth; Chandrasekharappa Settara C; Donovan Frank X; Zhou Weiyin; Hicks Belynda D; Boland Joseph F; Yeager Meredith; Jones Kristine; Zhu Bin; Wang Mingyi; Alter Blanche P; Savage Sharon A^*

来源：Journal of Medical Genetics, 2017, 54(6): 417-425.

DOI：10.1136/jmedgenet-2016-104346

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.

• 出版日期2017-6