Intron Retention Caused by a Novel Homozygous LNPK Splice‐Site Variant Leading to Severe Neurodevelopmental Disorder and Epilepsy

ABSTRACT Loss‐of‐function variants in LNPK have been shown to cause a neurodevelopmental syndrome associated with developmental delay, epilepsy, regression, and a distinct neuroimaging pattern including corpus callosum hypoplasia and abnormal T2/FLAIR hyperintensity at the tip of the frontal horn of the lateral ventricles (“ear‐of‐the‐lynx” sign). To date, 21 affected individuals from 16 families have been reported. Here, we identify a novel homozygous LNPK splice‐site variant (NM_030650.3:c.27 + 1G>T) in a patient with developmental delay, severe intellectual disability, epilepsy, and a brain MRI demonstrating corpus callosum hypoplasia, “ear‐of‐the‐lynx” sign, and substantia nigra signal alterations. To determine the variant's pathogenicity, we first used in silico splice prediction models AlphaGenome, SAI‐10 k‐calc, SpliceAI, and Pangolin. Then, by implementing targeted RNA sequencing of patient‐derived fibroblasts following nonsense‐mediated decay inhibition, we showed that the variant causes activation of a cryptic donor site, which results in a 5 bp intron retention and introduction of a premature stop codon into the transcript. We also delineate the phenotypic features of the proband with a comprehensive review of the literature. These findings expand the molecular spectrum of LNPK deficiency and demonstrate the complementary value of computational splicing prediction and functional RNA analysis for establishing the consequences of splice‐site variants in rare‐disease diagnostics.