ZMYND8 encodes a multidomain protein that is part of an extensive network of protein-protein interactions involved in transcription regulation, chromatin remodeling, super-enhancer regulation, DNA damage response, and tumor suppression. ZMYND8 was first reported in relation to autosomal dominant syndromic complex neurodevelopmental disorder in 2022 (Dias et al., PMID: 35916866). Most affected individuals present with mild to moderate intellectual disability, language deficits, variable dysmorphic facial features, congenital cardiac defects, skeletal anomalies, and hearing or visual impairment (PMID: 35916866). Other more variable features include autism spectrum disorder or autistic behavior, seizures, poor growth, and respiratory tract anomalies.
Thirteen variants (8 missense, 4 frameshift, and 1 nonsense) reported in 15 probands in five publications (PMIDs: 31981491, 32530565, 33057194, 35916866, 35982159) are included in this curation. All the variants with available parental information were de novo. The mechanism of pathogenicity is reported to be dominant negative for missense variants and loss of function for truncating variants (PMID: 35916866). All missense variants were located in functional domains or motifs; four variants were shown to affect the interaction with the neuronal actin-binding protein drebrin or with the NuRD complex subunit GATAD2A (PMID: 35916866).
This gene-disease relationship is also supported by a Drosophila model with neuronal knockdown of Zmynd8 that exhibits decreased habituation learning (PMID: 35916866).
In summary, there is strong evidence supporting the relationship between ZMYND8 and autosomal dominant syndromic complex neurodevelopmental disorder. Three years must elapse from the first proposal of the assertion to reach a definitive classification without any valid contradictory evidence. We will re-evaluate this gene-disease relationship at that time to determine if an upgraded classification of definitive is warranted. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on February 19, 2025 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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