Infantile Cirrhosis, Growth Impairment, and Neurodevelopmental Anomalies Associated with Deficiency of PPP1R15B.

01. Dezember, 2016

Mohammad S1, Wolfe LA2, Stöbe P3, Biskup S3, Wainwright MS4, Melin-Aldana H5, Malladi P1, Muenke M6, Gahl WA7, Whitington PF1.

Abstract

Objective:
To assess the utility of whole-exome sequencing (WES) in a sibling pair with undetermined liver disease and describe the phenotype associated with mutations discovered therein.

Study Design:
Next-generation WES was performed on 2 siblings (S1 and S2) who were born to nonconsanguineous parents of European extraction. Both siblings developed cirrhosis of indeterminate etiology and required liver transplantation; S1 at 7 months and S2 at 22 months.

Results:
Sequencing of germline DNA identified compound heterozygous mutations in PPP1R15B resulting in increased levels of phosphorylated eukaryotic translation initiation factor 2α.

Conclusions:
The first demonstration of PPP1R15B associated with liver disease expands the phenotypic spectrum of PPP1R15B related diseases. Our findings validate the application of WES in the diagnosis of children with undetermined liver disease. Understanding the genetic basis of liver disease may allow the development of targeted therapies for treatment and adequate counseling of families.

  1. Division of Gastroenterology, Department of Pediatrics, Feinberg School of Medicine of Northwestern University and Ann and Robert H Lurie Children’s Hospital of Chicago, Chicago, IL.
  2. National Institutes of Health Undiagnosed Diseases Program, Common Fund, National Institutes of Health, Bethesda, MD.
  3. Center for Genomics and Transcriptomics, Tuebingen, Germany.
  4. Division of Neurology, Department of Pediatrics, Feinberg School of Medicine of Northwestern University and Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL.
  5. Department of Pathology, Feinberg School of Medicine of Northwestern University and Ann and Robert H Lurie Children’s Hospital of Chicago, Chicago, IL.
  6. Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda MD.
  7. Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.