Ho-ho-ho! Gather ’round, my little elves, for a tale of scientific wonder that unfolded in the vast workshop of human biology. In a land where cells are the building blocks of life, there was a curious case of FIG4^-/- cells with lysosomes as plump as Christmas stockings overstuffed with goodies. But, oh dear, this swelling was no cause for joy, as it led to neurological and developmental disorders, as naughty as the Grinch on a Christmas Eve!

To save the day, our brave scientists embarked on a genome-wide activation screen, a magical sleigh ride across the genome, using CRISPR-a gene activation—think of it as the reindeer guiding the sleigh—to find the genes that could tame these bulbous lysosomes. With the help of fluorescence-activated cell sorting, a bit like sorting the naughty from the nice, they separated the corrected cells from the uncorrected ones.

And what to their wondering eyes did appear, but SLC12A9, a solute co-transporter, shining bright like a star atop the Christmas tree! When overexpressed, it corrected the lysosomal swelling in those mischievous FIG4^-/- cells. This SLC12A9, dressed in its best holiday attire, co-localized with LAMP2 at the lysosome membrane, like Santa cozying up to the fireplace.

But the plot thickens, like the plot of a Christmas Eve mystery! Biallelic variants of SLC12A9 were found in three unrelated probands, each with their own unique snowflake of neurodevelopmental disorders. These included intellectual disability and structural abnormalities, as if the blueprints for Santa’s toys had gone awry.

Patient 1, with a nonsense variant, was like a toy soldier missing a key part; patient 2, with a compound heterozygous variant, was like a puzzle with pieces from two different boxes; and proband 3, also compound heterozygous, was like a reindeer with mismatched antlers. Fibroblasts from patient 1, with their enlarged lysosomes, were corrected by the wildtype SLC12A9 cDNA, like a broken sleigh fixed by Santa’s elves.

Alas, one variant, p.(Asn552Lys), was like a string of Christmas lights with a bulb that wouldn’t light, failing to correct the lysosomal defect. It was clear that impaired function of SLC12A9 led to enlarged lysosomes and a recognizable neurodevelopmental phenotype, as distinct as Rudolph’s red nose.

So, my dear elves, let us cheer for the scientists who, with their clever minds and tools, uncovered the mysteries of SLC12A9, bringing hope to those affected by these conditions, much like Santa brings joy to children around the world on Christmas night. 🎅🔬🧬