UBTF was first reported in relation to autosomal dominant childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder in 2017 (Edvardson et al., PMID: 28777933). The phenotype consists of normal or mildly delayed early-neurodevelopment followed by progressive motor, cognitive, and behavioral regression in early-to-middle childhood (ranging from 2.5 to 7 years of age). Later features include profound intellectual disability, dysarthria progressing to aphasia, secondary microcephaly, spasticity, dystonia, gait ataxia, and loss of speech and ambulatory ability by the early teen years. Brain MRI shows progressive neurodegeneration, with cerebral and cerebellar atrophy, and involvement of both gray and white matter. A recurrent de novo missense variant, p.Glu210Lys (E210K), reported in 16 probands is included in this curation (PMIDs: 28777933, 29300972, 30517966, 31931739, 33026538, 36138999, 37162731). A different de novo missense variant was reported in a single proband with severe early-onset developmental delay and cerebral and cerebellar atrophy (PMID: 36106513); this variant has not been functionally validated and was not scored.
UBTF encodes a transcriptional activator of ribosomal RNA (rRNA) expression. The mechanism of pathogenicity appears to be gain-of-function, as suggested by studies in patient fibroblasts with the p.Glu210Lys variant showing increased UBF binding to the ribosomal DNA (rDNA) promoter and increased expression of pre-rRNA and 18S rRNA (PMIDs: 28777933, 29300972). However, studies in fibroblasts from homozygous Ubtf E210K knock-in mice revealed reduced association between UBTF1 and the RNA polymerase I transcription factor SL1 at the rDNA promoter and this correlated with a reduced rate of pre-rRNA synthesis as determined by metabolic labeling, suggesting a loss-of-function mechanism (PMID: 35139074). Additional experiments are needed to clarify the disease mechanism for this condition.
In summary, there is definitive evidence to support the relationship between UBTF and autosomal dominant childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on August 16, 2023 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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