A Description of Novel Variants and Review of Phenotypic Spectrum in UBA5-related Early Epileptic Encephalopathy.

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 compound heterozygous pathogenic variants in UBA5 and EIEE44. All five children presented with global developmental delay, axial hypotonia, appendicular hypertonia, and a movement disorder, including dystonia in four. Four of the five, including two siblings, have epilepsy. Affected individuals in all four families had compound heterozygous pathogenic variants in UBA5. All carry 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*), two 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 phenotype and genotype 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 add to the increasing understanding of epilepsy-movement disorders.