Mutations in two large pedigrees highlight the role of ZNF711 in X-linked intellectual disability

Abstract

Intellectual disability (ID) affects approximately 1-2% of the general population and is characterized by impaired cognitive abilities. ID is both clinically as well as genetically heterogeneous, up to 2000 genes are estimated to be involved in the emergence of the disease with various clinical presentations. For many genes, only a few patients have been reported and causality of some genes has been questioned upon the discovery of apparent loss-offunction mutations in healthy controls. Description of additional patients strengthens the evidence for the involvement of a gene in the disease and can clarify the clinical phenotype associated with mutations in a particular gene. Here, we present two large four-generation families with a total of 11 males affected with ID caused by mutations in ZNF711, thereby expanding the total number of families with ID and a ZNF711 mutation to four. Patients with mutations in ZNF711 all present with mild to moderate ID and poor speech accompanied by additional features in some patients, including autistic features and mild facial dysmorphisms, suggesting that ZNF711 mutations cause non-syndromic ID.

Periodic reanalysis of whole-genome sequencing data enhances the diagnostic advantage over standard clinical genetic testing

“…For the SNV in ZNF711, there was felt to be insufficient evidence in support of pathogenicity at the time of the initial review. The identification of additional cases has now bolstered the argument for causality [24].…”

A maternally inherited 8.05 Mb Xq21 deletion associated with Choroideremia, deafness, and mental retardation syndrome in a male patient

“…Clinical reports of sporadic cases also support this pathogenetic connection [11]. Recently in 11 male patients from two new found MRX97 families, Van der Welf et al [12] identified a frameshift deletion and a missence mutation in ZNF711 which both predict the deleterious effect and cause the disease. By expression analysis of cell culture, they also showed that these mutations induced differential expression of genes known to be expressed in the brain compared to controls, which adds evidence to ZNF711 as a transcription factor.…”

A Novel Chromosomal Translocation Identified due to Complex Genetic Instability in iPSC Generated for Choroideremia

“…There are twelve genes located within this duplication, half of which have been linked to a clinical phenotype. Although the exact function of the zinc finger protein ZNF711 is unknown, variants in this gene have been described as associated with cognitive disability [38]. Similarly, mutations in BRWD3 , which may have a chromatin-binding function, have been associated with cognitive disabilities [39,40], and the ribosomal S6-kinase, RPS6KA6 , is commonly deleted in patients with X-linked mental retardation [41].…”