ZMYND11 ‐related syndromic intellectual disability: 16 patients delineating and expanding the phenotypic spectrum
- 25 February 2020
- journal article
- research article
- Published by Hindawi Limited in Human Mutation
- Vol. 41 (5), 1042-1050
- https://doi.org/10.1002/humu.24001
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.This publication has 14 references indexed in Scilit:
- GeneMatcher: A Matching Tool for Connecting Investigators with an Interest in the Same GeneHuman Mutation, 2015
- Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular PathologyGenetics in Medicine, 2015
- Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research dataThe Lancet, 2014
- A de novo mutation in ZMYND11, a candidate gene for 10p15.3 deletion syndrome, is associated with syndromic intellectual disabilityEuropean Journal of Medical Genetics, 2014
- Refining analyses of copy number variation identifies specific genes associated with developmental delayNature Genetics, 2014
- ZMYND11 links histone H3.3K36me3 to transcription elongation and tumour suppressionNature, 2014
- Structural and Functional Analysis of the DEAF-1 and BS69 MYND DomainsPLOS ONE, 2013
- Subtelomeric deletion of chromosome 10p15.3: Clinical findings and molecular cytogenetic characterizationAmerican Journal of Medical Genetics Part A, 2012
- De Novo Gene Disruptions in Children on the Autistic SpectrumNeuron, 2012
- The adenovirus E1A binding protein BS69 is a corepressor of transcription through recruitment of N-CoROncogene, 2000