Congenital diarrhea disorders are a group of genetically diverse and typically autosomal recessive disorders that have yet to be well characterized phenotypically or molecularly. Diagnostic assessments are generally limited to nutritional challenges and histologic evaluation, and many subjects eventually require a prolonged course of intravenous nutrition. Here we describe next-generation sequencing techniques to investigate a child with perplexing congenital malabsorptive diarrhea and other presumably unrelated clinical problems; this method provides an alternative approach to molecular diagnosis.
We screened the diploid genome of an affected individual, using exome sequencing, for uncommon variants that have observed protein-coding consequences. We assessed the functional activity of the mutant protein, as well as its lack of expression using immunohistochemistry.
Among several rare variants detected was a homozygous nonsense mutation in the catalytic domain of the proprotein convertase subtilisin/kexin type 1 gene. The mutation abolishes prohormone convertase 1/3 endoprotease activity as well as expression in the intestine. These primary genetic findings prompted a careful endocrine reevaluation of the child at 4.5 years of age, and multiple significant problems were subsequently identified consistent with the known phenotypic consequences of proprotein convertase subtilisin/kexin type 1 (PCSK1) gene mutations. Based on the molecular diagnosis, alternate medical and dietary management was implemented for diabetes insipidus, polyphagia, and micropenis.
Whole-exome sequencing provides a powerful diagnostic tool to clinicians managing rare genetic disorders with multiple perplexing clinical manifestations.
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*Department of Human Genetics, David Geffen School of Medicine
†Department of Pediatrics, Division of Gastroenterology and Nutrition, Mattel Children's Hospital and David Geffen School of Medicine, University of California, Los Angeles
‡Department of Anatomy and Neurobiology, University of Maryland-Baltimore County, Baltimore, MD
¶Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles
#Department of Pediatrics, Division of Endocrinology, Mattel Children's Hospital and David Geffen School of Medicine, University of California, Los Angeles
**Department of Pediatrics, University of Nevada School of Medicine, Las Vegas
‡‡Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles.
Address correspondence and reprint requests to Martín G. Martín, MD, MPP, Department of Pediatrics, Division of Gastroenterology and Nutrition, Mattel Children's Hospital and the David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095 (e-mail: email@example.com).
Received 13 April, 2013
Accepted 7 August, 2013
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This work was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (#DK083762), and the California Institute of Regenerative Medicine RT2-01985, to M.G.M. and DA05084 to I.L.
The authors report no conflicts of interest.