2. Academic Validation
  3. Three rare diseases in one Sib pair: RAI1, PCK1, GRIN2B mutations associated with Smith-Magenis Syndrome, cytosolic PEPCK deficiency and NMDA receptor glutamate insensitivity

Three rare diseases in one Sib pair: RAI1, PCK1, GRIN2B mutations associated with Smith-Magenis Syndrome, cytosolic PEPCK deficiency and NMDA receptor glutamate insensitivity

  • Mol Genet Metab. 2014 Nov;113(3):161-70. doi: 10.1016/j.ymgme.2014.04.001.
David R Adams 1,  Hongjie Yuan 2,  Todd Holyoak 3,  Katrina H Arajs 3,  Parvin Hakimi 4,  Thomas C Markello 5,  Lynne A Wolfe 5,  Thierry Vilboux 6,  Barbara K Burton 7,  Karin Fuentes Fajardo 5,  George Grahame 8,  Conisha Holloman 9,  Murat Sincan 5,  Ann C M Smith 5,  Gordon A Wells 10,  Yan Huang 5,  Hugo Vega 5,  James P Snyder 11,  Gretchen A Golas 5,  Cynthia J Tifft 5,  Cornelius F Boerkoel 5,  Richard W Hanson 12,  Stephen F Traynelis 2,  Douglas S Kerr 13,  William A Gahl 14
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Pharmacology, Emory University School of Medicine, Rollins Research Center, Atlanta, GA, USA.
  • 3 Department of Biology, University of Waterloo, Waterloo, ON, Canada.
  • 4 Department of Biochemistry, Case Western Reserve University, USA; Department of Pediatrics, Case Western Reserve University, USA.
  • 5 Undiagnosed Diseases Program, Office of the Director, National Institutes of Health, Bethesda, MD, USA.
  • 6 Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD, USA.
  • 7 Ann and Robert H. Lurie Children's Hospital, Northwestern University, Chicago, IL, USA; Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  • 8 Center for Inherited Disorders of Energy Metabolism, University Hospitals Case Medical Center, Cleveland, OH, USA.
  • 9 University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
  • 10 Department of Chemistry, Emory University, Atlanta, GA, USA; Department of Biochemistry, University of Stellenbosch, South Africa.
  • 11 Department of Chemistry, Emory University, Atlanta, GA, USA.
  • 12 Department of Biochemistry, Case Western Reserve University, USA.
  • 13 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.
  • 14 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.
PMID: 24863970 DOI: 10.1016/j.ymgme.2014.04.001
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.

Keywords

Developmental delay; Dysmorphism; Hypoglycemia; Lactic acidemia; Multiple genetic disorders; Protein structure-function.

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