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

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, Thabo M. Yates and Morgan Drucker are Joint first authors. Meena Balasubramanian and Wen-Hann Tan are Joint senior authors.

ZMYND11 variants are a novel cause of centrotemporal and generalised epilepsies with neurodevelopmental disorder

“…Less frequent associations included micro‐ or macrocephaly, visual or hearing impairment. A broad but variable pattern of dysmorphism consistent with that already described 14 was present in only 12 individuals (Table 1) with some additional, previously unreported features including modified palmar crease, bushy eyebrows, thick digits and hypoplastic teeth (one individual each); the remaining eight individuals had no discernible facial dysmorphism. Neuroimaging findings revealed either no abnormalities or nonspecific features: prenatal infarct, ventricular enlargement/cerebral atrophy, delayed myelination, Chiari I abnormality (n = 2), glial scar; one individual had posterior polymicrogyria.…”

“…We identified individuals from Gene Matcher, 15 PubMed 6,8,14,16 the European Network Therapy Rare Epilepsies (NETRE), 17 and ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/), and the clinical information was systematically summarised by local clinicians. All individuals were tested using currently available next generation sequencing technology, either through whole exome sequencing or gene panels for neurodevelopmental disorders, 18 a few also with mitochondrial genome sequencing and deletion analysis (#2, #12, #16) 19 .…”

“…ZMYND11 encodes a transcriptional co‐repressor that interacts selectively with histone H3.3, also a focus for epilepsy associated genes CHD2 11 and SMARCA2 12 and itself recently linked to autism and seizures 13 . The ZMYND11 associated neurodevelopmental disorder phenotype was recently broadened to emphasise speech and language delay, with shared dysmorphic features 14 . However, the specific epilepsy associations with ZMYND11 have not been described and would have implications for diagnosis and treatment.…”

Case Report: Clinical Description of a Patient Carrying a 12.48 Mb Microdeletion Involving the 10p13–15.3 Region

“…Tumiene et al suggested that the clinical features of 10p15.3 microdeletion included neurodevelopmental disorders, characteristic dysmorphic features, and some other more frequent symptoms, and that the ZMYND11 gene was responsible for the above phenotype (24). As a transcriptional repressor, mutations of ZMYND11 have been associated with autosomal dominant mental retardation type 30 leading to intellectual disability, behavioral abnormalities, and seizures (25). Pathogenic single nucleotide variants (SNVs) of ZMYND11 were also associated with Cornelia de Lange syndrome in a large study (26).…”

Genomic Characteristics and Selection Signatures in Indigenous Chongming White Goat (Capra hircus)

“…For example, ZMYND11 variants were identified in mice with anxiety-like behavior (Parker et al, 2016). Pathogenic variants in ZMYND11 have been associated with intellectual disability, behavioral abnormalities, and seizures in humans (Yates et al, 2020).…”