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Hum Mutat. 2020 Feb 25. doi: 10.1002/humu.24001. [Epub ahead of print]

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

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Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK.
Department of Pediatrics, Johns Hopkins University, Baltimore, Maryland.
Northeast Thames Regional Genetics Service, Great Ormond Street Hospital for Children, London, UK.
Department of Clinical Genetics, St Michael's Hospital, Bristol, UK.
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK.
West Midlands Regional Clinical Genetics Service, Birmingham Health Partners Birmingham Women's Hospital NHS Foundation Trust, Birmingham, UK.
Département de Génétique, APHP, Hopital La Pitie Salpetriere, Paris, France.
Department of Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
South West Thames Regional Genetics Centre, St. George's Healthcare NHS Trust, St. George's, University of London, London, UK.
Congenica Limited, Biodata Innovation Centre, Wellcome Genome Campus, Cambridge, UK.
Department of Pediatrics, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, The Netherlands.
Department of Biomolecular Medicine, Ghent University, Ghent University Hospital, Center for Medical Genetics, Ghent, Belgium.
Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
Department of Oncology and Metabolism, Academic Unit of Child Health, University of Sheffield, Sheffield, UK.


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.


behavioral symptoms; gene expression regulation; intellectual disability; seizures; zinc fingers


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