AGTPBP1 was first reported in relation to autosomal recessive neurodegeneration, childhood-onset, with cerebellar atrophy (also known as Childhood-onset neurodegeneration with cerebellar atrophy (CONDCA)) in 2018 (Shashi et al., PMID: 30420557). Neurodegeneration, childhood-onset, with cerebellar atrophy is a severe neurodevelopmental disorder which presents in the first year of life with global developmental delay, impaired intellectual development, poor or absent speech, and motor abnormalities. Brain imaging shows cerebellar atrophy in patients with this disease. Biallelic variants in AGTPBP1 are reported to cause this disease through a loss of function mechanism.
Variants in this gene have also been associated with Pontocerebellar hypoplasia type 1. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found no difference in molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, the two disease entities have been lumped under neurodegeneration, childhood-onset, with cerebellar atrophy.
At least 13 unique variants (nonsense, missense, splice-site) that have been reported in 10 probands from 4 publications (PMIDs: 28600779, 30420557, 30976113, 38153683) are included in this curation. More information is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. This gene-disease relationship is also supported by biochemical function, functional alteration studies, and a knockout mouse model recapitulating the disease phenotype (PMIDs: 28325758, 30420557).
In summary, there is definitive evidence to support the relationship between AGTPBP1 and autosomal recessive neurodegeneration, childhood-onset, with cerebellar atrophy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Cerebral Palsy Gene Curation Expert Panel on July 21st, 2025 (SOP Version 11).
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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