The PRSS12 gene encodes a synaptic serine protease expressed in the brain. PRSS12 was first reported in relation to nonsyndromic intellectual disability in 2002 (Molinari et al., PMID: 12459588) in two families. Only one proband with a homozygous frameshift variant was scored. A second proband also carried the same homozygous frameshift variant, but both families originated from the same region of Eastern Algeria and were found to carry the variant on the same haplotype, so this individual was not scored. Segregation data was scored in Family 1, in which the variant was identified in a homozygous state in four affected siblings and in a heterozygous state in three unaffected siblings (PMID: 12459588).
Prss12 knockout mice showed no differences in behavioral tests of long-term memory, but had altered social interaction compared to wild-type mice (PMID: 20092579). In addition, knockout mice had reduced hippocampal apical spine density, reduced phosphorylated CREB after behavioral stimulation, and reduced activity-dependent formation of dendritic filopodia in the hippocampus (PMIDs: 20092579,19303856). The evidence from knockout mouse models was not scored as there is very limited case data, so the implication for a human phenotype is currently unclear.
In summary, there is limited evidence to support the relationship between PRSS12 and non-syndromic intellectual disability. 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 Intellectual Disability and Autism Gene Curation Expert Panel on August 4, 2021 (SOP Version 8).
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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