title: Diagnosis of D-Bifunctional Protein Deficiency through Whole-Genome Sequencing: Implications for Cost-Effective Care.
abstract: D-Bifunctional protein deficiency, caused by recessive mutations in HSD17B4, is a severe disorder of peroxisomal fatty acid oxidation. Nonspecific clinical features may contribute to diagnostic challenges. We describe a newborn female with infantile-onset seizures and nonspecific mild dysmorphisms who underwent extensive genetic workup that resulted in the detection of a novel homozygous mutation (c.302+1_4delGTGA) in the HSD17B4 gene, consistent with a diagnosis of D-bifunctional protein deficiency. By comparing the standard clinical workup to diagnostic analysis performed through research-based whole-genome sequencing (WGS), which independently identified the causative mutation, we demonstrated the ability of genomic sequencing to serve as a timely and cost-effective diagnostic tool for the molecular diagnosis of apparent and occult newborn diseases. As genomic sequencing becomes more available and affordable, we anticipate that WGS and related omics technologies will eventually replace the traditional tiered approach to newborn diagnostic workup.
authors.affiliation: Inova Translational Medicine Institute, Inova Health System, Falls Church, Va., USA.
authors.forename: Alina
authors.initials: A
authors.lastname: Khromykh
authors.affiliation: Inova Translational Medicine Institute, Inova Health System, Falls Church, Va., USA; Inova Children's Hospital, Inova Health System, Falls Church, Va., USA; Department of Pediatrics, Virginia Commonwealth University School of Medicine, Richmond, Va., USA.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Solomon
authors.affiliation: Inova Translational Medicine Institute, Inova Health System, Falls Church, Va., USA.
authors.forename: Dale L
authors.initials: DL
authors.lastname: Bodian
authors.affiliation: Division of Genetics and Metabolism, Children's National Medical Center, Washington, D.C., USA.
authors.forename: Eyby L
authors.initials: EL
authors.lastname: Leon
authors.affiliation: Inova Translational Medicine Institute, Inova Health System, Falls Church, Va., USA; Department of Obstetrics and Gynecology, Virginia Commonwealth University School of Medicine, Richmond, Va., USA.
authors.forename: Ramaswamy K
authors.initials: RK
authors.lastname: Iyer
authors.affiliation: Inova Children's Hospital, Inova Health System, Falls Church, Va., USA; Fairfax Neonatal Associates, Falls Church, Va., USA.
authors.forename: Robin L
authors.initials: RL
authors.lastname: Baker
authors.affiliation: Inova Children's Hospital, Inova Health System, Falls Church, Va., USA; Department of Pediatrics, Virginia Commonwealth University School of Medicine, Richmond, Va., USA.
authors.forename: David P
authors.initials: DP
authors.lastname: Ascher
authors.affiliation: Inova Children's Hospital, Inova Health System, Falls Church, Va., USA; Fairfax Neonatal Associates, Falls Church, Va., USA.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Baveja
authors.affiliation: Inova Translational Medicine Institute, Inova Health System, Falls Church, Va., USA; Fairfax Neonatal Associates, Falls Church, Va., USA.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Vockley
authors.affiliation: Inova Translational Medicine Institute, Inova Health System, Falls Church, Va., USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Niederhuber
keywords: Clinical workup; Cost-effective care; D-Bifunctional protein deficiency; Whole-genome sequencing