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dc.contributor.authorArnadottir, Gudny A
dc.contributor.authorJensson, Brynjar O
dc.contributor.authorMarelsson, Sigurdur E
dc.contributor.authorSulem, Gerald
dc.contributor.authorOddsson, Asmundur
dc.contributor.authorKristjansson, Ragnar P
dc.contributor.authorBenonisdottir, Stefania
dc.contributor.authorGudjonsson, Sigurjon A
dc.contributor.authorMasson, Gisli
dc.contributor.authorThorisson, Gudmundur A
dc.contributor.authorSaemundsdottir, Jona
dc.contributor.authorMagnusson, Olafur Th
dc.contributor.authorJonasdottir, Adalbjorg
dc.contributor.authorJonasdottir, Aslaug
dc.contributor.authorSigurdsson, Asgeir
dc.contributor.authorGudbjartsson, Daniel F
dc.contributor.authorThorsteinsdottir, Unnur
dc.contributor.authorArngrimsson, Reynir
dc.contributor.authorSulem, Patrick
dc.contributor.authorStefansson, Kari
dc.date.accessioned2017-11-20T15:03:10Z
dc.date.available2017-11-20T15:03:10Z
dc.date.issued2017-10-02
dc.date.submitted2017
dc.identifier.citationCompound heterozygous mutations in UBA5 causing early-onset epileptic encephalopathy in two sisters. 2017, 18 (1):103 BMC Med. Genet.en
dc.identifier.issn1471-2350
dc.identifier.pmid28965491
dc.identifier.doi10.1186/s12881-017-0466-8
dc.identifier.urihttp://hdl.handle.net/2336/620357
dc.descriptionTo access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Filesen
dc.description.abstractEpileptic 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.
dc.description.abstractWe 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.
dc.description.abstractWe 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.
dc.language.isoenen
dc.publisherBioMed Centralen
dc.relation.urlhttps://bmcmedgenet.biomedcentral.com/track/pdf/10.1186/s12881-017-0466-8?site=bmcmedgenet.biomedcentral.comen
dc.rightsArchived with thanks to BMC medical geneticsen
dc.subjectFlogaveikien
dc.subjectBörnen
dc.subjectPED12en
dc.subjectMAB12en
dc.subject.meshAdolescenten
dc.subject.meshAdulten
dc.subject.meshAge of Onseten
dc.subject.meshAmino Acid Substitutionen
dc.subject.meshChilden
dc.subject.meshChild, Preschoolen
dc.subject.meshEpilepsyen
dc.subject.meshFemaleen
dc.subject.meshHeterozygoteen
dc.subject.meshHumansen
dc.subject.meshInfanten
dc.subject.meshMutation, Missenseen
dc.subject.meshPedigreeen
dc.subject.meshSiblingsen
dc.subject.meshSpasms, Infantileen
dc.subject.meshUbiquitin-Activating Enzymesen
dc.titleCompound heterozygous mutations in UBA5 causing early-onset epileptic encephalopathy in two sisters.en
dc.typeArticleen
dc.contributor.department[ 1 ] deCODE Genet Amgen Inc, Sturlugata 8, IS-101 Reykjavik, Iceland Show the Organization-Enhanced name(s) [ 2 ] Landspitali Univ Hosp, Dept Pediat, Reykjavik, Iceland Show the Organization-Enhanced name(s) [ 3 ] Univ Iceland, Sch Engn & Nat Sci, Reykjavik, Iceland Show the Organization-Enhanced name(s) [ 4 ] Univ Iceland, Fac Med, Reykjavik, Iceland Show the Organization-Enhanced name(s) [ 5 ] Landspitali Univ Hosp, Dept Genet & Mol Med, Reykjavik, Icelanden
dc.identifier.journalBMC medical geneticsen
dc.rights.accessOpen Access - Opinn aðganguren
refterms.dateFOA2018-09-12T16:48:01Z
html.description.abstractEpileptic 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.
html.description.abstractWe 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.
html.description.abstractWe 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.


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