Biallelic deleterious variants in SNAPIN, a retrograde dynein adaptor, cause a prenatal-onset neurodevelopmental disorder [1]

Fetal brain anomalies identified by prenatal ultrasound and/or magnetic resonance imaging represent a considerable healthcare burden with ~1-2/1,000 live births. To identify underlying etiology, trio prenatal exome sequencing or genome sequencing (ES/GS) has emerged as a comprehensive diagnostic paradigm with a reported diagnostic rate up to ~32%. Here, we report five unrelated families with six affected cases that presented neuroanatomical, craniofacial, and skeletal anomalies, all harboring rare, biallelic deleterious variants in SNAPIN, encoding SNARE-associated protein. SNAPIN is a ubiquitously expressed component of the autophagy-lysosomal pathway that catalyzes retrograde axonal transport and synaptic transmission. To investigate the role of SNAPIN in brain development, we generated zebrafish gene ablation models, which recapitulated human-relevant disease phenotypes. Two independent, genetically stable snapin mutants exhibited pre-adulthood lethality, reduced overall length, disproportionately smaller head size, and altered brain morphology. Transcriptomic profiling of snapin mutant zebrafish heads revealed an early and progressive transcriptomic shift marked by autophagy activation with concomitant downregulation of structural and neurodevelopmental genes. Assessment of brain cellular ultrastructure with electron microscopy and LC3-II immunoblotting revealed retrograde vesicle transport defects, with accumulation of late endosomes and autophagosomes. Together, these findings support SNAPIN as a likely causal gene for a severe neurodevelopmental syndrome and expand the growing list of autophagy-lysosome pathway regulators essential for human brain development. Overall design: To investigate the impact of snapin dysfunction in an in vivo neurodevelopmental context, we performed transcriptomics studies using RNA isolated from heads of snapin 9bpdel-2bpins homozygous mutants and wild type zebrafish larvae at 10 dpf (two biological replicates each).