Submission Details

ZNF711 was first reported in relation to X-linked complex neurodevelopmental disorder (NDD) in 2009 by Tarpey et al. (PMID: 19377476) who reported a frameshift and nonsense variant transmitted within two large pedigrees with several affected males with intellectual disability and no other observable phenotypes. van der Werf et al. (2017, PMID: 27993705) reported two multigenerational families with X-linked complex NDD segregating with ZNF711 variants (frameshift and missense). Four additional ZNF711 variants were reported by Wang et al. (2022, PMID: 34992252); 3 nonsense variants and one de novo missense variant observed in families or individual probands affected by X-linked complex NDD. Segregation evidence from Tarpey et al. (2009), van der Werf et al. (2017), and Wang et al. (2022) resulted in 3 additional points. The maximum score for genetic evidence (12 points) was reached. Of note, missense variants in individual probands were of unclear pathogenicity and were not scored (PMIDs: 25649377, 28135719). An additional novel variant (c.127_129delGTT, p.V43del, GRCh37/hg19; ClinVar SCV:002030756.1) has been identified in a family affected by X-linked complex NDD enrolled in the Brain Gene Registry, but was not scored at this time.

Experimental evidence implicates ZNF711 in a regulatory network of syntenic, X-linked neurodevelopmental disorder-associated genes (KDM5C, ARX, PHF8) based on a series of studies demonstrating spatiotemporal expression patterns in developing human and mouse brains (PMID: 34356104), protein interactions (PMID: 31691806, PMID: 20346720), functional alteration in patient-derived cells (PMID: 34356104), and rescue experiments in cell culture models (PMID: 34356104 , PMID: 31691806) that are consistent with observed clinical phenotypes.

In summary, there is definitive evidence supporting the relationship between ZNF711 and X-linked complex neurodevelopmental disorder. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on November 3, 2020. It was reevaluated on September 22, 2022 (SOP Version 9). As a result of this reevaluation, the classification increased from Moderate to Definitive with the addition of new cases and experimental evidence.

ZNF711 was first reported in relation to X-linked complex neurodevelopmental disorder (NDD) in 2009 by Tarpey et al. (PMID: 19377476) who reported a frameshift and nonsense variant transmitted within two large pedigrees with several affected males with intellectual disability and no other observable phenotypes. van der Werf et al. (2017, PMID: 27993705) reported two multigenerational families with X-linked complex NDD segregating with ZNF711 variants (frameshift and missense). Four additional ZNF711 variants have been reported by Wang et al. (2022, PMID: 34992252); 3 nonsense variants and one de novo missense variant observed in families or individual probands affected by X-linked complex NDD. Segregation evidence from Tarpey et al. (2009), van der Werf et al. (2017), and Wang et al. (2022) resulted in 3 additional points. The maximum genetic evidence score (12 points) was reached. Of note, missense variants in individual probands were of unclear pathogenicity and were not scored (PMIDs: 25649377, 28135719). An additional novel variant (c.127_129delGTT, p.V43del, GRCh37/hg19) (ClinVar SCV:002030756.1) has been identified in a family affected by X-linked complex NDD enrolled in the Brain Gene Registry, but was not scored at this time.

Experimental evidence implicates ZNF711 in a regulatory network of syntenic, X-linked neurodevelopmental disorder-associated genes (KDM5C, ARX, PHF8) based on a series of studies demonstrating spatiotemporal expression patterns in developing human and mouse brains (PMID: 34356104), protein interactions (PMID: 31691806, PMID: 20346720), functional alteration in patient-derived cells (PMID: 34356104), and rescue experiments in cell culture models (PMID: 34356104 , PMID: 31691806) that are consistent with observed clinical phenotypes. Three points were given for the experimental evidence, bringing the total to 15 points.

Given supportive evidence from multiple publications over 13 years, there is definitive evidence to support the relationship between ZNF711 and X-linked complex neurodevelopmental disorder.

Note: This gene was originally curated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 11/3/2020. It was reevaluated on 9/22/2022 (SOP 9). New genetic evidence described additional cases and families harboring ZNF711 variants and additional experimental evidence was added. As a result, the classification was changed from moderate to definitive.