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A description of novel variants and review of phenotypic spectrum in UBA5 -related early epileptic encephalopathy.
- Source :
-
Cold Spring Harbor molecular case studies [Cold Spring Harb Mol Case Stud] 2021 Jun 11; Vol. 7 (3). Date of Electronic Publication: 2021 Jun 11 (Print Publication: 2021). - Publication Year :
- 2021
-
Abstract
- Early infantile epileptic encephalopathy-44 (EIEE44, MIM: 617132) is a previously described condition resulting from biallelic variants in UBA5 , a gene involved in a ubiquitin-like post-translational modification system called UFMylation. Here we report five children from four families with biallelic pathogenic variants in UBA5 All five children presented with global developmental delay, epilepsy, axial hypotonia, appendicular hypertonia, and a movement disorder, including dystonia in four. Affected individuals in all four families have compound heterozygous pathogenic variants in UBA5 All have the recurrent mild c.1111G > A (p.Ala371Thr) variant in trans with a second UBA5 variant. One patient has the previously described c.562C > T (p. Arg188*) variant, two other unrelated patients have a novel missense variant, c.907T > C (p.Cys303Arg), and the two siblings have a novel missense variant, c.761T > C (p.Leu254Pro). Functional analyses demonstrate that both the p.Cys303Arg variant and the p.Leu254Pro variants result in a significant decrease in protein function. We also review the phenotypes and genotypes of all 15 previously reported families with biallelic UBA5 variants, of which two families have presented with distinct phenotypes, and we describe evidence for some limited genotype-phenotype correlation. The overlap of motor and developmental phenotypes noted in our cohort and literature review adds to the increasing understanding of genetic syndromes with movement disorders-epilepsy.<br /> (© 2021 Briere et al.; Published by Cold Spring Harbor Laboratory Press.)
- Subjects :
- Adolescent
Brain diagnostic imaging
Brain physiology
Child
Cohort Studies
Epilepsy genetics
Female
Genetic Association Studies
HEK293 Cells
Humans
Male
Muscle Hypotonia
Mutation, Missense
Proteins genetics
Proteins metabolism
Spasms, Infantile diagnostic imaging
Spasms, Infantile pathology
Young Adult
Phenotype
Spasms, Infantile genetics
Spasms, Infantile metabolism
Ubiquitin-Activating Enzymes genetics
Ubiquitin-Activating Enzymes metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2373-2873
- Volume :
- 7
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cold Spring Harbor molecular case studies
- Publication Type :
- Academic Journal
- Accession number :
- 33811063
- Full Text :
- https://doi.org/10.1101/mcs.a005827