ZMIZ1 – Neurodevelopmental Disorder with Dysmorphic Facies and Distal Skeletal Anomalies

Neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies (NEDDFSA) is an autosomal dominant syndrome characterized by facial dysmorphism, distal skeletal anomalies, and global developmental delay, caused by heterozygous pathogenic variants in ZMIZ1 on chromosome 10q22.3. To date, 32 unrelated probands with de novo ZMIZ1 variants have been reported, with consistent phenotypes across diverse populations (PMID:35432459). The core clinical features include telecanthus, blepharophimosis, myopia, cryptorchidism, joint hypermobility, and hallux valgus.

Genetic evidence comprises 32 probands harboring de novo variants—predominantly missense (n=27), in‐frame deletions (n=3), and splice‐site changes (n=2)—in ZMIZ1. Representative pathogenic alleles include c.2330G>A (p.Gly777Glu) identified in exon 20 (PMID:35432459), c.858_875del (p.Val288_Ala293del) associated with reduced protein expression in a Chinese family (PMID:38117436), and c.881C>T (p.Thr294Ile) linked to novel ocular findings (PMID:39658964).

Functional assays provide moderate evidence: the in‐frame deletion p.Val288_Ala293del causes a significant decrease in ZMIZ1 protein levels by western blot and immunofluorescence, supporting a haploinsufficiency mechanism (PMID:38117436). Computational and splicing analyses of missense alleles predict disruption of the MIZ/SP‐RING zinc‐finger domain and altered protein conformation (PMID:35432459).

In vivo, a forebrain‐specific Zmiz1 knockout mouse model recapitulates key human features including cortical microcephaly, corpus callosum dysgenesis, and autistic‐like behaviors. Transcriptomic profiling reveals disrupted neurogenesis and synaptic signaling, and EFNB2 treatment rescues dendritic outgrowth deficits, underscoring a dosage‐sensitive role for ZMIZ1 in cortical development (PMID:39211117).

No conflicting or refuting evidence has been reported. The convergence of genetic and experimental data supports a strong autosomal dominant association between ZMIZ1 variants and NEDDFSA. Key take‐home: Heterozygous pathogenic variants in ZMIZ1 cause NEDDFSA via haploinsufficiency, facilitating precise molecular diagnosis and informed genetic counseling.

References

• Frontiers in Genetics • 2022 • A de Novo ZMIZ1 Pathogenic Variant for Neurodevelopmental Disorder With Dysmorphic Facies and Distal Skeletal Anomalies. PMID:35432459
• Ophthalmic Genetics • 2025 • A novel ZMIZ1 variant associated with NEDDFSA and new ocular features: case report and review of literature. PMID:39658964
• Genes & Genomics • 2024 • Clinical report and genetic analysis of a novel variant in ZMIZ1 causing neurodevelopmental disorder with dysmorphic factors and distal skeletal anomalies in a Chinese family. PMID:38117436
• bioRxiv • 2024 • Loss of Zmiz1 in mice leads to impaired cortical development and autistic-like behaviors. PMID:39211117

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