Novel and known ribosomal causes of Diamond-Blackfan anaemia identified through comprehensive genomic characterisation.
J Med Genet
; 54(6): 417-425, 2017 06.
Article
em En
| MEDLINE
| ID: mdl-28280134
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 IdentifierNCT00027274), 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.Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Ribossomos
/
Anemia de Diamond-Blackfan
/
Mutação
Tipo de estudo:
Etiology_studies
/
Incidence_studies
/
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Limite:
Adolescent
/
Adult
/
Aged
/
Aged80
/
Child
/
Child, preschool
/
Female
/
Humans
/
Infant
/
Male
Idioma:
En
Revista:
J Med Genet
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Estados Unidos