Autosomal dominant inheritance in a recently described ZMIZ1‐related neurodevelopmental disorder: Case report of siblings and an affected parent

Abstract

ZMIZ1, zinc finger MIZ‐domain containing 1, has recently been described in association with syndromic intellectual disability in which the primary phenotypic features include intellectual disability/developmental delay, seizures, hearing loss, behavioral issues, failure to thrive, and various congenital malformations. Most reported cases have been found to result from de novo mutations except for one set of three siblings in which parental testing could not be performed. With informed consent from the family, we report on a father and his two sons demonstrating autosomal dominant inheritance of a novel pathogenic ZMIZ1 variant, c.1310delC (p.Pro437ArgfsX84), causing this recently described neurodevelopmental syndrome. While they all show syndromic findings along with short stature and intellectual disability, only one child had sensorineural hearing loss. Moreover, severity of intellectual disability and eyelid ptosis were variable among the affected members. Our report demonstrates that phenotypic features of ZMIZ1‐related neurodevelopmental syndrome are variable even within the same family and that parental testing to identify a mildly affected parent is needed.

Compound Heterozygote of Point Mutation and Chromosomal Microdeletion Involving OTUD6B Coinciding with ZMIZ1 Variant in Syndromic Intellectual Disability

“…To date, 15 pathogenic, or likely pathogenic, ZMIZ1 variants have been described in 18 families, most of which represent de novo events. Two families were reported with dominantly inherited mutations and intra-familial variability [11,12].…”

“…Given clinical similarities of the phenotypes, caused by biallelic mutations of OTUD6B and heterozygous ZMIZ1 mutations, and that the present patient harbored genetic defects of these two genes, we compared the phenotypes of the present patient to those in previous reports, as summarized in Table 1 [5][6][7][8][9][10][11][12].…”

“…Heterozygous ZMIZ1 variants have been found to be associated with neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies (NEDDFSA), including infantile hypotonia, seizures, and ID of varying severity. Since the first description of ZMIZ1 as the cause of ID, in 2019, only a handful of cases have been reported, most of which represented de novo occurrences; only two families were reported with inherited mutations [11,12].…”

A de Novo ZMIZ1 Pathogenic Variant for Neurodevelopmental Disorder With Dysmorphic Facies and Distal Skeletal Anomalies

“…Seven distinct regions were identified, one alanine-rich region (aa280-305, E-score = 2.1E-06), two proline-rich regions (aa334-555, E-score = 3.9E-16; aa867-1002, E-score = 3.8E-07), one bipartite nuclear localization signal (NLS, aa697-711, E-score = 2.1E+04), MIZ/SP-RING zinc finger (aa738-787, E-score = 1.1E-33), and one copper binding octapeptide (aa947-954, E-value = 1.5). All variants of ZMIZ1 were also recruited from the DECIPHER database ( Swaminathan et al, 2012 ) and the four published articles ( Córdova-Fletes et al, 2015 ; Carapito et al, 2019 ; Latchman et al, 2020 ; Phetthong et al, 2021 ). A total of 33 patients with ZMIZ1 pathogenic variants were collected, 1 from our current cohort ( Figures 4A,B ), 8 from the DECIPHER database ( Figure 4C ), and 24 from published articles ( Figure 4D ).…”

“…Later, in 2019, pathogenic variants involving the gene ZMIZ1 were identified in a cohort of 19 NEDDFSA cases from a transatlantic collaborative effort ( Carapito et al, 2019 ). In the same year of 2019, an affected father and his two sons were identified to be suffering from the ZMIZ1-related neurodevelopmental disorder in Florida ( Latchman et al, 2020 ). In 2021, Phetthong et al reported a 5-year-old Thai girl with developmental delay, facial phenotypes resembling Williams syndrome, and cardiac defects.…”