Journal
MOLECULAR GENETICS AND METABOLISM
Volume 113, Issue 3, Pages 161-170Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ymgme.2014.04.001
Keywords
Hypoglycemia; Lactic acidemia; Dysmorphism; Developmental delay; Protein structure-function; Multiple genetic disorders
Funding
- Intramural Research Program of the National Human Genome Research Institute [NS036654]
- NIH Undiagnosed Diseases Program [HSN268201300162P]
- Center for Inherited Disorders of Energy Metabolism
- Allison Foundation [116491]
- National Center for Research Resources [P20 RR17708]
- Natural Sciences and Engineering Research Council of Canada
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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 RAII 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. (C) 2014 Elsevier Inc. All rights reserved.
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