title: Three rare diseases in one Sib pair: RAI1, PCK1, GRIN2B mutations associated with Smith-Magenis Syndrome, cytosolic PEPCK deficiency and NMDA receptor glutamate insensitivity.
abstract: The National Institutes of Health Undiagnosed Diseases Program evaluates patients for whom no diagnosis has been discovered despite a comprehensive diagnostic workup. Failure to diagnose a condition may arise from the mutation of genes previously unassociated with disease. However, we hypothesized that this could also co-occur with multiple genetic disorders. Demonstrating a complex syndrome caused by multiple disorders, we report two siblings manifesting both similar and disparate signs and symptoms. They shared a history of episodes of hypoglycemia and lactic acidosis, but had differing exam findings and developmental courses. Clinical acumen and exome sequencing combined with biochemical and functional studies identified three genetic conditions. One sibling had Smith-Magenis Syndrome and a nonsense mutation in the RAI1 gene. The second sibling had a de novo mutation in GRIN2B, which resulted in markedly reduced glutamate potency of the encoded receptor. Both siblings had a protein-destabilizing homozygous mutation in PCK1, which encodes the cytosolic isoform of phosphoenolpyruvate carboxykinase (PEPCK-C). In summary, we present the first clinically-characterized mutation of PCK1 and demonstrate that complex medical disorders can represent the co-occurrence of multiple diseases.
authors.affiliation: Undiagnosed Diseases Program, Office of the Director, National Institutes of Health, Bethesda, MD, USA; Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD, USA. Electronic address: david.adams@nih.gov.
authors.forename: David R
authors.initials: DR
authors.lastname: Adams
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Rollins Research Center, Atlanta, GA, USA.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Department of Biology, University of Waterloo, Waterloo, ON, Canada.
authors.forename: Todd
authors.initials: T
authors.lastname: Holyoak
authors.affiliation: Department of Biology, University of Waterloo, Waterloo, ON, Canada.
authors.forename: Katrina H
authors.initials: KH
authors.lastname: Arajs
authors.affiliation: Department of Biochemistry, Case Western Reserve University, USA; Department of Pediatrics, Case Western Reserve University, USA.
authors.forename: Parvin
authors.initials: P
authors.lastname: Hakimi
authors.affiliation: Undiagnosed Diseases Program, Office of the Director, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Markello
authors.affiliation: Undiagnosed Diseases Program, Office of the Director, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Lynne A
authors.initials: LA
authors.lastname: Wolfe
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD, USA.
authors.forename: Thierry
authors.initials: T
authors.lastname: Vilboux
authors.affiliation: Ann and Robert H. Lurie Children's Hospital, Northwestern University, Chicago, IL, USA; Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Burton
authors.affiliation: Undiagnosed Diseases Program, Office of the Director, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Karin Fuentes
authors.initials: KF
authors.lastname: Fajardo
authors.affiliation: Center for Inherited Disorders of Energy Metabolism, University Hospitals Case Medical Center, Cleveland, OH, USA.
authors.forename: George
authors.initials: G
authors.lastname: Grahame
authors.affiliation: University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
authors.forename: Conisha
authors.initials: C
authors.lastname: Holloman
authors.affiliation: Undiagnosed Diseases Program, Office of the Director, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Murat
authors.initials: M
authors.lastname: Sincan
authors.affiliation: Undiagnosed Diseases Program, Office of the Director, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Ann C M
authors.initials: AC
authors.lastname: Smith
authors.affiliation: Department of Chemistry, Emory University, Atlanta, GA, USA; Department of Biochemistry, University of Stellenbosch, South Africa.
authors.forename: Gordon A
authors.initials: GA
authors.lastname: Wells
authors.affiliation: Undiagnosed Diseases Program, Office of the Director, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Undiagnosed Diseases Program, Office of the Director, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Hugo
authors.initials: H
authors.lastname: Vega
authors.affiliation: Department of Chemistry, Emory University, Atlanta, GA, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
authors.affiliation: Undiagnosed Diseases Program, Office of the Director, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Gretchen A
authors.initials: GA
authors.lastname: Golas
authors.affiliation: Undiagnosed Diseases Program, Office of the Director, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Tifft
authors.affiliation: Undiagnosed Diseases Program, Office of the Director, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Cornelius F
authors.initials: CF
authors.lastname: Boerkoel
authors.affiliation: Department of Biochemistry, Case Western Reserve University, USA.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Hanson
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Rollins Research Center, Atlanta, GA, USA.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Traynelis
authors.affiliation: Department of Biochemistry, Case Western Reserve University, USA; Department of Pediatrics, Case Western Reserve University, USA; Center for Inherited Disorders of Energy Metabolism, University Hospitals Case Medical Center, Cleveland, OH, USA.
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Kerr
authors.affiliation: Undiagnosed Diseases Program, Office of the Director, National Institutes of Health, Bethesda, MD, USA; Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000172:deficiency*; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D058496:Smith-Magenis Syndrome / Q000175:diagnosis* / Q000235:genetics; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C121001:NR2B NMDA receptor; C431552:RAI1 protein, human; D016194:Receptors, N-Methyl-D-Aspartate; D015534:Trans-Activators; D014157:Transcription Factors; C521898:PCK1 protein, human; D010729:Phosphoenolpyruvate Carboxykinase (GTP); C000597251:PCK2 protein, human; D019764:Phosphoenolpyruvate Carboxykinase (ATP)
keywords: Developmental delay; Dysmorphism; Hypoglycemia; Lactic acidemia; Multiple genetic disorders; Protein structure-function