Compound heterozygous mutations in UBA5 causing early-onset epileptic encephalopathy in two sisters.

Autor:	Arnadottir GA; deCODE Genetics/Amgen, Inc., Sturlugata 8, 101, Reykjavik, Iceland., Jensson BO; deCODE Genetics/Amgen, Inc., Sturlugata 8, 101, Reykjavik, Iceland., Marelsson SE; Department of Pediatrics, Landspitali University Hospital, Reykjavik, Iceland., Sulem G; deCODE Genetics/Amgen, Inc., Sturlugata 8, 101, Reykjavik, Iceland., Oddsson A; deCODE Genetics/Amgen, Inc., Sturlugata 8, 101, Reykjavik, Iceland., Kristjansson RP; deCODE Genetics/Amgen, Inc., Sturlugata 8, 101, Reykjavik, Iceland., Benonisdottir S; deCODE Genetics/Amgen, Inc., Sturlugata 8, 101, Reykjavik, Iceland., Gudjonsson SA; deCODE Genetics/Amgen, Inc., Sturlugata 8, 101, Reykjavik, Iceland., Masson G; deCODE Genetics/Amgen, Inc., Sturlugata 8, 101, Reykjavik, Iceland., Thorisson GA; deCODE Genetics/Amgen, Inc., Sturlugata 8, 101, Reykjavik, Iceland., Saemundsdottir J; deCODE Genetics/Amgen, Inc., Sturlugata 8, 101, Reykjavik, Iceland., Magnusson OT; deCODE Genetics/Amgen, Inc., Sturlugata 8, 101, Reykjavik, Iceland., Jonasdottir A; deCODE Genetics/Amgen, Inc., Sturlugata 8, 101, Reykjavik, Iceland., Jonasdottir A; deCODE Genetics/Amgen, Inc., Sturlugata 8, 101, Reykjavik, Iceland., Sigurdsson A; deCODE Genetics/Amgen, Inc., Sturlugata 8, 101, Reykjavik, Iceland., Gudbjartsson DF; deCODE Genetics/Amgen, Inc., Sturlugata 8, 101, Reykjavik, Iceland.; School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland., Thorsteinsdottir U; deCODE Genetics/Amgen, Inc., Sturlugata 8, 101, Reykjavik, Iceland.; Faculty of Medicine, University of Iceland, Reykjavik, Iceland., Arngrimsson R; Department of Genetics and Molecular Medicine, Landspitali University Hospital, Reykjavik, Iceland., Sulem P; deCODE Genetics/Amgen, Inc., Sturlugata 8, 101, Reykjavik, Iceland. patrick.sulem@decode.is., Stefansson K; deCODE Genetics/Amgen, Inc., Sturlugata 8, 101, Reykjavik, Iceland.; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
Jazyk:	angličtina
Zdroj:	BMC medical genetics [BMC Med Genet] 2017 Oct 02; Vol. 18 (1), pp. 103. Date of Electronic Publication: 2017 Oct 02.
DOI:	10.1186/s12881-017-0466-8
Abstrakt:	Background: Epileptic encephalopathies are a group of childhood epilepsies that display high phenotypic and genetic heterogeneity. The recent, extensive use of next-generation sequencing has identified a large number of genes in epileptic encephalopathies, including UBA5 in which biallelic mutations were first described as pathogenic in 2016 (Colin E et al., Am J Hum Genet 99(3):695-703, 2016. Muona M et al., Am J Hum Genet 99(3):683-694, 2016). UBA5 encodes an activating enzyme for a post-translational modification mechanism known as ufmylation, and is the first gene from the ufmylation pathway that is linked to disease. Case Presentation: We sequenced the genomes of two sisters with early-onset epileptic encephalopathy along with their unaffected parents in an attempt to find a genetic cause for their condition. The sisters, born in 2004 and 2006, presented with infantile spasms at six months of age, which later progressed to recurrent, treatment-resistant seizures. We detected a compound heterozygous genotype in UBA5 in the sisters, a genotype not seen elsewhere in an Icelandic reference set of 30,067 individuals nor in public databases. One of the mutations, c.684G > A, is a paternally inherited exonic splicing mutation, occuring at the last nucleotide of exon 7 of UBA5. The mutation is predicted to disrupt the splice site, resulting in loss-of-function of one allele of UBA5. The second mutation is a maternally inherited missense mutation, p.Ala371Thr, previously reported as pathogenic when in compound heterozygosity with a loss-of-function mutation in UBA5 and is believed to produce a hypomorphic allele. Supportive of this, we have identified three adult Icelanders homozygous for the p.Ala371Thr mutation who show no signs of neurological disease. Conclusions: We describe compound heterozygous mutations in the UBA5 gene in two sisters with early-onset epileptic encephalopathy. To our knowledge, this is the first description of mutations in UBA5 since the initial discovery that pathogenic biallelic variants in the gene cause early-onset epileptic encephalopathy. We further provide confirmatory evidence that p.Ala371Thr is a hypomorphic mutation, by presenting three adult homozygotes who show no signs of neurological disease.
Databáze:	MEDLINE
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