A de novo missense mutation in ZMYND11 is associated with global developmental delay, seizures, and hypotonia

Abstract

Recently, mutations in the zinc finger MYND-type containing 11 (ZMYND11) gene were identified in patients with autism spectrum disorders, intellectual disability, aggression, and complex neuropsychiatric features, supporting that this gene is implicated in 10p15.3 microdeletion syndrome. We report a novel de novo variant in the ZMYND11 gene (p.Ser421Asn) in a patient with a complex neurodevelopmental phenotype. The patient is a 24-yr-old Caucasian/Filipino female with seizures, global developmental delay, sensorineural hearing loss, hypotonia, dysmorphic features, and other features including a happy disposition and ataxic gait similar to Angelman syndrome. In addition, this patient had uncommon features including eosinophilic esophagitis and multiple, severe allergies not described in similar ZMYND11 cases. This new case further supports the association of ZMYND11 with autistic-like phenotypes and suggests that ZMYND11 should be included in the list of potentially causative candidate genes in cases with complex neurodevelopmental phenotypes.

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

“…ZMYND11 protein showing pathogenic variants in this series (below protein) and previously reported (above protein; Cobben et al, 2014; Coe et al, 2014; Iossifov et al, 2012; Moskowitz et al, 2016; Popp et al, 2017) (transcript NM_006624.5, Human Genome Build GRCh37.p13). Functional domains are labeled according to their location in the protein.…”

“…All patients (including our series) had DD, particularly affecting speech and ID. The severity of ID in this series is mild to moderate, but four patients have previously been described with severe ID (Cobben et al, 2014; Coe et al, 2014; Moskowitz et al, 2016; Popp et al, 2017). Behavioral issues are also a prominent feature both in our series and in those previously published (Coe et al, 2014; Popp et al, 2017), including aggression, attention deficit/hyperactivity, and autism/autistic traits.…”

“…Here, we present 16 new individuals with predicted pathogenic variants in ZMYND11 . Comparison with all previously published patients allows further delineation of the phenotypic spectrum associated with mutations in this gene (Tables 2 and S1; Aoi et al, 2019; Cobben et al, 2014; Coe et al, 2014; Iossifov et al, 2012; Moskowitz et al, 2016; Popp et al, 2017).…”

“…In support of the critical role of ZMYND11 in the chromosome 10p15.3 microdeletion syndrome, patients with de novo truncating variants in ZMYND11 have a similar phenotype, including ID, seizures, and behavioral issues (Coe et al, 2014; Popp et al, 2017). In addition, missense variants in this gene have also been associated with ID and seizures, although there is a more severe phenotype in patients with specific variants, which may be related to a gain‐of‐function mechanism (Cobben et al, 2014; Moskowitz et al, 2016). A splice site variant has also been reported in a child with autism spectrum disorder (Iossifov et al, 2012).…”

“…A splice site variant has also been reported in a child with autism spectrum disorder (Iossifov et al, 2012). In total, 11 patients with pathogenic variants in ZMYND11 (MIM# 616083) have been reported to date (Aoi et al, 2019; Cobben et al, 2014; Coe et al, 2014; Iossifov et al, 2012; Moskowitz et al, 2016; Popp et al, 2017).…”