NAV3 – Autosomal Recessive Neurodevelopmental Disorder

Neuron navigator 3 (NAV3) is a cytoskeleton‐associated ATPase highly expressed in embryonic and adult brain, implicated in axonal guidance, neuronal migration, and neurite outgrowth. While NAV3 had not been definitively linked to human disease, recent reports describe bi‐allelic truncating variants in individuals with global developmental delay, intellectual disability, dysmorphism, and behavioral abnormalities, establishing a novel neurodevelopmental syndrome ([PMID:39708122]).

Multi‐patient studies initially described 12 probands from eight unrelated families with bi‐allelic and mono‐allelic NAV3 variants presenting with neurodevelopmental disorder ([PMID:39708122]). The current study adds five patients from three consanguineous families segregating autosomal recessive disease, yielding a total of 17 unrelated probands from 11 families with biallelic NAV3 variants ([PMID:39708122]). Segregation analysis in three pedigrees (two affected siblings in one kindred and singletons in two others) confirmed co‐segregation of NAV3 truncating alleles in four affected relatives.

Identified variants include homozygous nonsense mutations c.6325C>T (p.Gln2109Ter) and c.6577T>C (p.Arg2193Ter) as well as a canonical splice‐site alteration, all predicted to generate loss of function ([PMID:39708122]). An independent Saudi proband harbored a bi‐allelic frameshift variant c.2604_2605del (p.Val870SerfsTer12), with RT-qPCR demonstrating significantly reduced NAV3 transcript levels and 3D protein modeling predicting disruption of AAA and coiled‐coil domains ([PMID:39038237]).

Single-cell RNA sequencing of human embryonic and young adult brains revealed high NAV3 expression in excitatory neurons, inhibitory neurons, and microglia, concordant with the observed neurodevelopmental phenotype ([PMID:39708122]). Functional studies thus support a loss-of-function mechanism underlying the recessive disorder.

Collectively, 17 probands with bi-allelic truncating NAV3 variants, segregation in multiple consanguineous families, and concordant functional data provide Strong clinical validity for NAV3 in autosomal recessive neurodevelopmental disorder. Additional replication and accumulation of missense or hypomorphic alleles may further refine the phenotypic spectrum. Key take-home: NAV3 truncating variants are reliable molecular markers for diagnostic testing in early‐onset neurodevelopmental delay and intellectual disability.

References

• Human genetics • 2025 • Further evidence of biallelic NAV3 variants associated with recessive neurodevelopmental disorder with dysmorphism, developmental delay, intellectual disability, and behavioral abnormalities. PMID:39708122
• Molecular genetics & genomic medicine • 2024 • Mutated neuron navigator 3 as a candidate gene for a rare neurodevelopmental disorder. PMID:39038237

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