TY - JOUR
T1 - D-bifunctional protein deficiency caused by splicing variants in a neonate with severe peroxisomal dysfunction and persistent hypoglycemia
AU - Werner, Kelly M.
AU - Cox, Allison J.
AU - Qian, Emily
AU - Jain, Preti
AU - Ji, Weizhen
AU - Tikhonova, Irina
AU - Castaldi, Christopher
AU - Bilguvar, Kaya
AU - Knight, James
AU - Ferdinandusse, Sacha
AU - Fawaz, Rima
AU - Jiang, Yong-Hui
AU - Gallagher, Patrick G.
AU - Bizzarro, Matthew
AU - Gruen, Jeffrey R.
AU - Bale, Allen
AU - Zhang, Hui
N1 - Funding Information: WGS, WES, and RNA-seq were performed at the Yale Center for Genome Analysis. Testing of very-long-chain fatty acids, urine organic acids, and plasma amino acids were performed at ARUP Laboratories, Salt Lake City, Utah. Fibroblast studies were performed at Amsterdam University Medical Center, the Netherlands. The authors thank the patient's family for their contributions. Publisher Copyright: © 2021 Wiley Periodicals LLC
PY - 2022/1
Y1 - 2022/1
N2 - 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.
AB - 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.
KW - D-bifunctional protein deficiency
KW - Zellweger spectrum disorders
KW - peroxisomal biogenesis disorders
KW - rapid whole genome sequencing
KW - very-long-chain fatty acids
UR - http://www.scopus.com/inward/record.url?scp=85116526259&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/ajmg.a.62520
DO - https://doi.org/10.1002/ajmg.a.62520
M3 - Article
C2 - 34623748
SN - 1552-4825
VL - 188
SP - 357
EP - 363
JO - American journal of medical genetics. Part A
JF - American journal of medical genetics. Part A
IS - 1
ER -