Bi-allelic ATG12 variants impair autophagy and cause a neurodevelopmental disorder.

Impaired ATG12-ATG5 conjugate formation and reduced autophagic flux (congenital autophagy disorder)

ATG12, encoding a core autophagy effector, is identified as a novel Mendelian NDD gene through bi-allelic variants in six individuals from five families. The neurological phenotype closely overlaps with ATG5 and ATG7-related congenital autophagy disorders: developmental delay, intellectual disability, congenital ataxia, hypotonia, seizures, and cerebellar vermis hypoplasia. Biochemical analyses of primary fibroblasts confirmed loss of the ATG12-ATG5 conjugate and altered autophagic flux. Yeast complementation studies and zebrafish models demonstrated conserved disruption of autophagy and brain development defects.

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This work reinforces the emerging class of congenital autophagy disorders. With ATG5, ATG7, and now ATG12, all three central autophagosome formation effectors are linked to human disease, sharing a recognizable phenotype of ataxia, NDD, and cerebellar hypoplasia. ATG gene testing should be considered in unexplained congenital ataxia and NDD without identified etiology.

Clinical impact : 2/3 · Evidence strength : 2/3 · Novelty : 2/2 · Sample size : 1/1 · Journal quality : 1/1 → Total : 8/10