ATP6V1B2‐related epileptic encephalopathy

ATP6V1B2 encodes a subunit of the lysosomal transmembrane proton pump necessary for adequate functioning of several acid hydrolases. De novo monoallelic variants of this gene have been associated with two distinct phenotypes: Zimmermann‐Laband syndrome 2 (ZLS2), an intellectual deficiency/multiple malformation syndrome, and dominant deafness onychodystrophy (DDOD), a multiple malformation syndrome without cognitive involvement. Epilepsy is not observed in DDOD, is variably present in ZLS2, but is a common feature in Zimmermann‐Laband syndrome 1 (ZLS1) (caused by monoallelic pathogenic variants in KCNH1) and Zimmermann‐Laband syndrome‐like (ZLSL) (associated with KCNK4 variants). Herein, we report a case of an infant with severe epileptic encephalopathy with microcephaly and profound developmental delay, associated with a novel de novo loss‐of‐function variant in ATP6V1B2, diagnosed by whole‐exome sequencing. This finding expands the spectrum of ATP6V1B2‐associated disorders and adds ATP6V1B2 as a new member for the growing list of early‐onset epileptic encephalopathy genes. [Published with video sequence].