A functional assay for the clinical annotation of genetic variants of uncertain significance in Diamond-Blackfan anemia.

Human Mutation
Anna AspesiIrma Dianzani

Abstract

Diamond-Blackfan anemia (DBA) is a rare genetic hypoplasia of erythroid progenitors characterized by mild to severe anemia and associated with congenital malformations. Clinical manifestations in DBA patients are quite variable and genetic testing has become a critical factor in establishing a diagnosis of DBA. The majority of DBA cases are due to heterozygous loss-of-function mutations in ribosomal protein (RP) genes. Causative mutations are fairly straightforward to identify in the case of large deletions and frameshift and nonsense mutations found early in a protein coding sequence, but diagnosis becomes more challenging in the case of missense mutations and small in-frame indels. Our group recently characterized the phenotype of lymphoblastoid cell lines established from DBA patients with pathogenic lesions in RPS19 and observed that defective pre-rRNA processing, a hallmark of the disease, was rescued by lentiviral vectors expressing wild-type RPS19. Here, we use this complementation assay to determine whether RPS19 variants of unknown significance are capable of rescuing pre-rRNA processing defects in these lymphoblastoid cells as a means of assessing the effects of these sequence changes on the function of the RPS19 prot...Continue Reading

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Citations

Dec 6, 2018·British Journal of Haematology·Marije Bartels, Marc Bierings
Feb 23, 2020·British Journal of Haematology·Paola QuarelloUNKNOWN AIEOP working group on Diamond Blackfan Anaemia
Jan 1, 2021·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Marcello CeciNicla Romano

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Methods Mentioned

BETA
transfection
PCR

Software Mentioned

NNSplice
MaxEntScan
Mutation Assessor
NetGene2
GeneSplicer
Polyphen
MutationTaster
Human Splicing Finder
Mutation Taster
Provean

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