Submission Details

At the time of evaluation, ZC3H14 variants have been reported in a single publication in 2011 describing individuals with autosomal recessive intellectual disability (PMID: 21734151). ZC3H14 encodes a zinc finger CCCH domain-containing protein 14 that belongs to a family of poly(A)-binding proteins that influence gene expression. Three siblings with mild-moderate intellectual disability in a consanguineous family were reported with a homozygous nonsense ZC3H14 variant (PMID: 21734151). An additional consanguineous family with 3 siblings with severe intellectual disability harbouring a homozygous intronic ZC3H14 variant was also reported in 2011 (PMID: 21734151); however, this variant was found at a high frequency in gnomAD v2.1.1 (2.8% in the Ashkenazi Jewish population) and was not scored. Homozygous ZC3H14 knock-out mouse and drosophila (null dNab2 ortholog) demonstrate impaired poly(A) tail length, expression of synaptic proteins, and impaired brain function and development (PMIDs: 21734151, 28666327). In summary, there is limited evidence at this time to support the relationship between ZC3H14 and autosomal recessive intellectual disability. Additional studies are required to verify this gene-disease relationship. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on November 16, 2022 (SOP Version 9).