Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Case Reports
. 2017 Oct 2;18(1):103.
doi: 10.1186/s12881-017-0466-8.

Compound Heterozygous Mutations in UBA5 Causing Early-Onset Epileptic Encephalopathy in Two Sisters

Free PMC article
Case Reports

Compound Heterozygous Mutations in UBA5 Causing Early-Onset Epileptic Encephalopathy in Two Sisters

Gudny A Arnadottir et al. BMC Med Genet. .
Free PMC article


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.

Keywords: Case report; Epileptic encephalopathy; Exonic splicing mutation; Hypomorphic mutation; UBA5; Ufmylation.

Conflict of interest statement

Ethics approval and consent to participate

The study was approved by the National Bioethics Committee in Iceland. Written, informed consent to participate was obtained for all participants, or their guardians, before blood samples were drawn.

Consent for publication

All participants, or their guardians, provided written informed consent for publication of medical data, medical imaging and genetic data.

Competing interests

GAA, BOJ, GS, AO, RPK, SB, SAG, GM, GAT, JS, OTM, AJ, ASJ, AS, DFG, UT, PS and KS are full-time employees of deCODE Genetics/Amgen, Inc. SEM and RA declare no conflict of interest.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


Fig. 1
Fig. 1
Pedigree of the two affected sisters. Family members are represented by their birth years. The affection status of the sisters is indicated by filled symbols. The status of the two UBA5 (NM_024818.3) mutations is provided below each family member, where red refers to the status of the missense mutation, p.Ala371Thr (m1), blue refers to the status of the exonic splicing mutation, c.684G > A (m2), and the plus sign (+) refers to the wild-type allele

Similar articles

See all similar articles

Cited by 3 articles


    1. McTague A, Howell KB, Cross JH, Kurian MA, Scheffer IE. The genetic landscape of the epileptic encephalopathies of infancy and childhood. Lancet Neurol. 2016;15(3):304–316. doi: 10.1016/S1474-4422(15)00250-1. - DOI - PubMed
    1. Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD). 1995–2017. Accessed May 2017.
    1. Colin E, Daniel J, Ziegler A, et al. Biallelic variants in UBA5 reveal that disruption of the UFM1 Cascade can result in early-onset encephalopathy. Am J Hum Genet. 2016;99(3):695–703. doi: 10.1016/j.ajhg.2016.06.030. - DOI - PMC - PubMed
    1. Muona M, Ishimura R, Laari A, et al. Biallelic variants in UBA5 link dysfunctional UFM1 ubiquitin-like modifier pathway to severe infantile-onset encephalopathy. Am J Hum Genet. 2016;99(3):683–694. doi: 10.1016/j.ajhg.2016.06.020. - DOI - PMC - PubMed
    1. Gudbjartsson DF, Helgason H, Gudjonsson SA, et al. Large-scale whole-genome sequencing of the Icelandic population. Nat Genet. 2015;47(5):435–444. doi: 10.1038/ng.3247. - DOI - PubMed

Publication types


LinkOut - more resources