Congenital ataxia due to novel variant in ATP8A2

Congenital ataxias are a heterogeneous group of disorders characterized by congenital or early‐onset ataxia. Here, we describe two siblings with congenital ataxia, who acquired independent gait by age 4 years. After 16 years of follow‐up they presented near normal cognition, cerebellar ataxia, mild...

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Bibliographic Details
Published in:Clinical genetics 2021-07, Vol.100 (1), p.79-83
Main Authors: Damásio, Joana, Santos, Diana, Morais, Sara, Brás, José, Guerreiro, Rita, Sardoeira, Ana, Cavaco, Sara, Carrilho, Inês, Barbot, Clara, Barros, José, Sequeiros, Jorge
Format: Article
Language:English
Subjects:
Adenosine Triphosphatases - genetics
Adult
Ataxia
ATP8A2
Bioinformatics
Cell Line
Cerebellar ataxia
Cerebellar Ataxia - genetics
Cerebellum
Cloning vectors
Codon, Nonsense - genetics
Cognition
Congenital diseases
Dystonia
Female
Gait
Genetic Variation - genetics
HEK293 Cells
hereditary ataxia
Homozygote
Humans
intronic variant
Introns - genetics
Male
minigene assay
Nonsense mutation
Pedigree
Phospholipid Transfer Proteins - genetics
RNA Splice Sites - genetics
RNA Splicing - genetics
Stop codon
Transcription
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Summary:Congenital ataxias are a heterogeneous group of disorders characterized by congenital or early‐onset ataxia. Here, we describe two siblings with congenital ataxia, who acquired independent gait by age 4 years. After 16 years of follow‐up they presented near normal cognition, cerebellar ataxia, mild pyramidal signs, and dystonia. On exome sequencing, a novel homozygous variant (c.1580‐18C > G ‐ intron 17) in ATP8A2 was identified. A new acceptor splice site was predicted by bioinformatics tools, and functionally characterized through a minigene assay. Minigene constructs were generated by PCR‐amplification of genomic sequences surrounding the variant of interest and cloning into the pCMVdi vector. Altered splicing was evaluated by expressing these constructs in HEK293T cells. The construct with the c.1580‐18C > G homozygous variant produced an aberrant transcript, leading to retention of 17 bp of intron 17, by the use of an alternative acceptor splice site, resulting in a premature stop codon by insertion of four amino acids. These results allowed us to establish this as a disease‐causing variant and expand ATP8A2‐related disorders to include less severe forms of congenital ataxia.
ISSN:0009-9163
1399-0004
DOI:10.1111/cge.13954