D-bifunctional
protein (DBP) deficiency is a rare, autosomal recessive peroxisomal
enzyme deficiency resulting in a high burden of morbidity and early mortality. Patients with DBP deficiency resemble those with a severe Zellweger phenotype, with
neonatal hypotonia,
seizures, craniofacial dysmorphisms, psychomotor delay,
deafness, blindness, and death typically within the first 2 years of life, although patients with residual
enzyme function can survive longer. The clinical severity of the disease depends on the degree of
enzyme deficiency. Loss-of-function variants typically result in no residual
enzyme activity; however, splice variants may result in
protein with residual function. We describe a full-term newborn presenting with
hypotonia,
seizures, and unexplained
hypoglycemia, who was later found to have
rickets at follow up. Rapid whole genome sequencing identified two HSD17B4 variants in trans; one likely pathogenic variant and one variant of uncertain significance (VUS) located in the polypyrimidine tract of intron 13. To determine the functional consequence of the VUS, we analyzed
RNA from the patient's father with
RNA-seq which showed skipping of Exon 14, resulting in a frameshift mutation three
amino acids from the new reading frame. This
RNA-seq analysis was correlated with virtually absent
enzyme activity, elevated very-long-chain
fatty acids in fibroblasts, and a clinically severe phenotype. Both variants are reclassified as pathogenic. Due to the clinical spectrum of DBP deficiency, this provides important prognostic information, including early mortality. Furthermore, we add persistent
hypoglycemia to the clinical spectrum of the disease, and advocate for the early management of fat-soluble
vitamin deficiencies to reduce complications.