ZMYND11 ZMYND11 ‐related syndromic intellectual disability: 16 patients delineating and expanding the phenotypic spectrum

摘要

Abstract Pathogenic variants in ZMYND11 , which acts as a transcriptional repressor, have been associated with intellectual disability, behavioral abnormalities, and seizures. Only 11 affected individuals have been reported to date, and the phenotype associated with pathogenic variants in this gene have not been fully defined. Here, we present 16 additional patients with predicted pathogenic heterozygous variants in including four individuals from the same family, to further delineate and expand the genotypic and phenotypic spectrum of ZMYND11 ‐related syndromic intellectual disability. The associated phenotype includes developmental delay, particularly affecting speech, mild‐moderate intellectual disability, significant behavioral abnormalities, seizures, and hypotonia. There are subtle shared dysmorphic features, including prominent eyelashes and eyebrows, a depressed nasal bridge with bulbous nasal tip, anteverted nares, thin vermilion of the upper lip, and wide mouth. Novel features include brachydactyly and tooth enamel hypoplasia. Most identified variants are likely to result in premature truncation and/or nonsense‐mediated decay. Two ZMYND11 variants located in the final exon—p.(Gln586*) (likely escaping nonsense‐mediated decay) and p.(Cys574Arg)—are predicted to disrupt the MYND‐type zinc‐finger motif and likely interfere with binding to its interaction partners. Hence, the homogeneous phenotype likely results from a common mechanism of loss‐of‐function.