ZMIZ1 – Syndromic Intellectual Disability

ZMIZ1 encodes a transcriptional co-activator recently implicated in autosomal dominant syndromic intellectual disability (PMID:31833199). Affected individuals present with global developmental delay, seizures, hearing impairment, failure to thrive, short stature, ptosis, and variable congenital anomalies. While most reported cases arise from de novo variants, familial transmission has been documented, underscoring the need for parental testing. Experimental studies in animal and cellular models demonstrate a critical role for ZMIZ1 in neurogenesis, synaptic connectivity, and cortical development. Here, we evaluate genetic and functional evidence linking ZMIZ1 to MONDO:0000508 and outline its clinical utility.

Inheritance is autosomal dominant. In one pedigree, a heterozygous frameshift variant, c.1310delC (p.Pro437ArgfsTer84), segregated in a father and his two affected sons with variable intellectual disability and eyelid ptosis (PMID:31833199). In a second family, a heterozygous splice-site change, c.1491+2T>C, leading to exon 14 skipping, was present in a proband and her father with overlapping neurodevelopmental and dysmorphic features (PMID:34680978).

To date, four probands across two independent families have been reported, with segregation in two additional relatives, establishing a recurrent variant spectrum of loss-of-function alleles, including frameshift and splice-site changes (PMID:31833199, PMID:34680978). This pattern supports haploinsufficiency as the primary mechanism. Additional isolated de novo cases in the literature further reinforce this association, although these were beyond the supplied evidence.

Functional studies provide concordant support. Forebrain-specific Zmiz1 knockout mice develop cortical microcephaly, corpus callosum dysgenesis, and impaired differentiation of upper-layer neurons, phenocopying human clinical features (PMID:39211117). Behavioral assays reveal autism-like alterations in motor activity, social interaction, and communication, consistent with the syndromic spectrum.

Complementary work shows that Zmiz1 is enriched in embryonic cortex, hippocampus, and cerebellum in mice and humans, aligning with disease-relevant expression domains (PMID:38686122). Rescue of dendritic outgrowth deficits in Zmiz1 mutant neurons by exogenous EFNB2 demonstrates a direct mechanistic link and highlights a potential therapeutic avenue (PMID:39211117).

Collectively, genetic and experimental data fulfill ClinGen criteria for a Strong gene–disease association. ZMIZ1 testing should be integrated into diagnostic panels for syndromic intellectual disability to guide clinical management and genetic counseling. Key Take-home: ZMIZ1 haploinsufficiency via autosomal dominant loss-of-function variants causes syndromic intellectual disability, supported by familial segregation and robust functional validation.

References

• American journal of medical genetics. Part A • 2020 • Autosomal dominant inheritance in a recently described ZMIZ1-related neurodevelopmental disorder: Case report of siblings and an affected parent. PMID:31833199
• Genes • 2021 • Compound Heterozygote of Point Mutation and Chromosomal Microdeletion Involving OTUD6B Coinciding with ZMIZ1 Variant in Syndromic Intellectual Disability. PMID:34680978
• Frontiers in psychiatry • 2024 • Zmiz1 is a novel regulator of brain development associated with autism and intellectual disability. PMID:38686122
• bioRxiv • 2024 • Loss of Zmiz1 in mice leads to impaired cortical development and autistic-like behaviors. PMID:39211117

Evidence Based Scoring (AI generated)