Titel: Further delineation of the ZNF292-associated phenotypic spectrum
ID: P-MonoG-142
Art: Postertalk
Redezeit: 2 min
Session: Poster Session

Referent: Miriam Bertrand (Tübingen/DE)

Abstract - Text



Heterozygous loss-of-function variants in ZNF292 coding for zinc finger protein 292 have been recently associated with a neurodevelopmental disorder (NDD) characterized by variable intellectual disability with speech delays and nonspecific syndromic features (MIM #619188, MRD64). We aimed to determine the prevalence of pathogenic ZNF292 variants in national and international cohorts and to investigate the associated phenotypic spectrum.


An in-house database containing >15,000 exome and genome datasets including about 3,200 from patients with syndromic or nonsyndromic NDDs was searched for rare loss-of-function variants in ZNF292. Additional rare disease cohorts were queried by calls for collaboration within the European Solve-RD and ERN ITHACA networks as well as through personal communication. Patients were examined by local clinicians and clinical and molecular data were collected in a standardized table. Facial characteristics of patients with available photographs were analyzed using the Face2Gene RESEARCH application.


Our search with stringent filtering criteria performed on the in-house database prioritized seven loss-of-function ZNF292 variants in NDD individuals while no comparable variants were detected in patients with unrelated phenotypes or healthy individuals. Additional patients carrying pathogenic ZNF292 variants were identified by collaborative efforts for a total of 20 previously unreported patients from 16 independent families. Main clinical characteristics included language delay, variable intellectual disability, behavioral abnormalities, and mild facial dysmorphisms with additional syndromic features in a subset of patients. The mutational spectrum comprised one splice site, six stop-gain, and eight frameshift variants leading to a premature termination codon. All changes were absent from the gnomAD browser and predicted to be deleterious by CADD scoring. Of note, in two of the four familial cases, ZNF292 variants were inherited from mothers with a very mild cognitive impairment which would have gone unnoticed without targeted thorough re-phenotyping upon the diagnoses of their sons.


We provide further evidence for the association of loss-of-function variants in ZNF292 with an autosomal dominant intellectual developmental disorder with variable expressivity. Our data suggest that pathogenic ZNF292 variants might represent a more common cause of NDD with mild to moderate intellectual disability.