Krabbe disease variant classification using parental blood-based diagnostic RNA-seq

Krabbe disease (KD) is a rare autosomal recessive lysosomal storage disorder (LSD) associated with severe neurodegeneration and high mortality and is one of most prevalent LSDs at a recent estimate of 1 in 12,080 live births. The disease pathogenesis is related to low/undetectable galactocerebrosidase (GALC) activity resulting in an accumulation of a cytotoxic GALC substrate, psychosine (Psy), that leads to diffuse demyelination, psychomotor delays, and high morbidity/mortality across the disease spectrum. Although phenotypic prediction in newborns with a more common, homozygous 30kb deletion and very high Psy levels is straightforward, there is a larger subset of patients identified through newborn screening with missense variants of uncertain significance (VUSs) that present with mildly elevated Psy levels that are difficult to interpret. Functional data for a small set of missense variants support altered GALC trafficking and lysosomal localization in KD compared to a loss of catalyt...