title: A compound heterozygous mutation in GPD1 causes hepatomegaly, steatohepatitis, and hypertriglyceridemia.
abstract: The constellation of clinico-pathological and laboratory findings including massive hepatomegaly, steatosis, and marked hypertriglyceridemia in infancy is extremely rare. We describe a child who is presented with the above findings, and despite extensive diagnostic testing no cause could be identified. Whole exome sequencing was performed on the patient and parents' DNA. Mutations in GPD1 encoding glycerol-3-phosphate dehydrogenase that catalyzes the reversible redox reaction of dihydroxyacetone phosphate and NADH to glycerol-3-phosphate (G3P) and NAD(+) were identified. The proband inherited a GPD1 deletion from the father determined using copy number analysis and a missense change p.(R229Q) from the mother. GPD1 protein was absent in the patient's liver biopsy on western blot. Low normal activity of carnitine palmitoyl transferases, CPT1 and CPT2, was present in the patient's skin fibroblasts, without mutations in genes encoding for these proteins. This is the first report of compound heterozygous mutations in GPD1 associated with a lack of GPD1 protein and reduction in CPT1 and CPT2 activity.
authors.affiliation: 1] Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA [2] The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Mugdha
authors.initials: M
authors.lastname: Joshi
authors.affiliation: 1] Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA [2] Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA [3] The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Eagan
authors.affiliation: Division of Gastroenterology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Nirav K
authors.initials: NK
authors.lastname: Desai
authors.affiliation: 1] Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA [2] The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Newton
authors.affiliation: 1] Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA [2] The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Meghan C
authors.initials: MC
authors.lastname: Towne
authors.affiliation: 1] Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA [2] The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Marinakis
authors.affiliation: 1] Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA [2] Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA [3] The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Kristyn M
authors.initials: KM
authors.lastname: Esteves
authors.affiliation: Department of Cardiology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: De Ferranti
authors.affiliation: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bennett
authors.affiliation: Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
authors.forename: Adam
authors.initials: A
authors.lastname: McIntyre
authors.affiliation: 1] Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA [2] The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Alan H
authors.initials: AH
authors.lastname: Beggs
authors.affiliation: 1] Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA [2] The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Gerard T
authors.initials: GT
authors.lastname: Berry
authors.affiliation: 1] Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA [2] Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA [3] The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Pankaj B
authors.initials: PB
authors.lastname: Agrawal
mesh_terms: D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism; D002648:Child; D056915:DNA Copy Number Variations; D005234:Fatty Liver / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D055106:Genome-Wide Association Study; D050536:Glycerol-3-Phosphate Dehydrogenase (NAD+) / Q000235:genetics* / Q000378:metabolism; D006529:Hepatomegaly / Q000175:diagnosis / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D015228:Hypertriglyceridemia / Q000175:diagnosis / Q000235:genetics*; D007223:Infant; D009154:Mutation; D017422:Sequence Analysis, DNA
chemical_list: D050536:Glycerol-3-Phosphate Dehydrogenase (NAD+); C577474:CPT1A protein, human; D002334:Carnitine O-Palmitoyltransferase