NPTX1 was first associated with autosomal dominant cerebellar ataxia in 2022 (Coutelier M, et al., PMID: 34788392). The NPTX1 gene is a member of the neuronal pentraxin family and encodes a long neuronal pentraxin protein. It has various cellular and synaptic functions including mediating the uptake of synaptic material and presynaptic toxins (PMID: 8884281). The reported phenotype is characterized by a slowly progressive gait ataxia, oculomotor apraxia and other eye movement abnormalities, and cerebellar atrophy on brain imaging. Other features may be present as well and onset is typically, but not always, in adulthood (PMID: 20301317).
Four missense variants that have been reported in 8 probands across 3 publications (PMIDs: 34788392, 35285082, 35560436) are included in this curation. One variant, c.1165G>A (p.Gly389Arg), was reported in five of the probands, but was excluded as a founder variant after haplotype analysis was performed (PMID: 34788392). The mechanism of pathogenicity is unclear.
This gene-disease relationship is supported by expression studies showing that this gene is expressed in the central nervous system, with highest expression in the cerebellum (PMIDs: 34788392, 32913098).
In summary, there is presently limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Cerebellar Ataxia GCEP on the meeting date September 11, 2024 (SOP Version 10).
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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