Bi-allelic deleterious variants in SNAPIN, which encodes a retrograde dynein adaptor, cause a prenatal-onset neurodevelopmental disorder.

Abstract

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 the 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 individuals that presented neuroanatomical, craniofacial, and skeletal anomalies, all harboring rare, bi-allelic deleterious variants in SNAPIN, which encodes 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 light chain 3 (LC3)-II immunoblotting revealed retrograde vesicle transport defects, with an accumulation of late endosomes and autophagosomes. Together, these findings support bi-allelic pathogenic variants in SNAPIN as a likely cause for a severe neurodevelopmental syndrome and expand the growing list of autophagy-lysosome pathway regulators essential for human brain development.