A description of novel variants and review of phenotypic spectrum in <i>UBA5</i>-related early epileptic encephalopathy

Lauren C. Briere, Melissa A. Walker, Frances A. High, Cynthia Cooper, Cassandra A. Rogers, Christine J. Callahan, Ryosuke Ishimura, Yoshinobu Ichimura, Paul A. Caruso, Nutan Sharma, Elly Brokamp, Mary E. Koziura, Shekeeb S. Mohammad, Russell C. Dale, Lisa G. Riley, John A. Phillips, Masaaki Komatsu, David A. Sweetser

doi:10.1101/mcs.a005827

<jats:p>Early infantile epileptic encephalopathy-44 (EIEE44, MIM: 617132) is a previously described condition resulting from biallelic variants in <jats:italic>UBA5</jats:italic>, 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 <jats:italic>UBA5</jats:italic>. 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 <jats:italic>UBA5</jats:italic>. All have the recurrent mild c.1111G > A (p.Ala371Thr) variant in <jats:italic>trans</jats:italic> with a second <jats:italic>UBA5</jats:italic> 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 <jats:italic>UBA5</jats:italic> 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.</jats:p>

A description of novel variants and review of phenotypic spectrum in <i>UBA5</i>-related early epileptic encephalopathy

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