BLOC1S1 variants cause lysosomal and autophagic defects resulting in a hypomyelinating leukodystrophy with epileptic encephalopathy

<i>BLOC1S1</i> encodes a subunit shared by the BLOC-1 and BORC hetero-octameric complexes that regulate various endolysosomal processes. Here, we report the identification of seven distinct variants in <i>BLOC1S1</i> in eleven individuals from seven independent families presenting with early psychomotor delay, hypotonia, spasticity, epileptic encephalopathy, optic atrophy, and leuko-axonopathy with hypomyelination. A subset of the affected individuals also have features of hypopigmentation and ocular albinism that are similar, although milder, than those of individuals with BLOC-1-related Hermansky-Pudlak syndrome. Functional analyses show that <i>BLOC1S1</i> knockout (KO) impairs the anterograde transport of lysosomes and autophagy in both non-neuronal cells and iPSC-derived neurons. Rescue experiments reveal that most <i>BLOC1S1</i> variants exhibit reduced expression, decreased assembly with other BORC/BLOC-1 subunits, and/or impaired restoration of lysosome transport and autophagy in <i>BLOC1S1</i>-KO cells. Additionally, we show that KO of <i>BLOC1S1</i> reduces pigmentation in a melanocytic cell line, and that five of the <i>BLOC1S1</i> variants partially or fully restore pigmentation. These findings provide genetic, clinical, and functional evidence that loss-of-function (LoF) of <i>BLOC1S1</i> leads to more pronounced deficits in BORC than BLOC-1 function. We conclude that the biallelic <i>BLOC1S1</i> variants characterized here primarily result in a neurological disorder with prominent leukodystrophy, similar to the recently reported condition caused by variants in the BORCS8 subunit of BORC. Together, these findings establish BORCopathies as a distinct disease entity.