Case Reports

. 2014 Oct;16(10):751-8.

doi: 10.1038/gim.2014.22. Epub 2014 Mar 20.

Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway

Gregory M Enns¹, Vandana Shashi², Matthew Bainbridge³, Michael J Gambello⁴, Farah R Zahir⁵, Thomas Bast⁶, Rebecca Crimian², Kelly Schoch², Julia Platt¹, Rachel Cox¹, Jonathan A Bernstein¹, Mena Scavina⁷, Rhonda S Walter⁸, Audrey Bibb⁴, Melanie Jones⁴, Madhuri Hegde⁴, Brett H Graham³, Anna C Need⁹, Angelica Oviedo¹⁰, Christian P Schaaf¹¹, Sean Boyle¹², Atul J Butte¹², Rui Chen¹³, Rong Chen¹², Michael J Clark¹², Rajini Haraksingh¹²; FORGE Canada Consortium; Tina M Cowan¹⁴, Ping He¹⁵, Sylvie Langlois⁵, Huda Y Zoghbi¹⁶, Michael Snyder¹², Richard A Gibbs¹⁷, Hudson H Freeze¹⁵, David B Goldstein¹⁸

Collaborators, Affiliations

Collaborators

FORGE Canada Consortium:
Kym Boycott, Jan Friedman, Jacques Michaud, Francois Bernier, Michael Brudno, Bridget Fernandez, Bartha Knoppers, Mark Samuels, Steve Scherer

Affiliations

¹ Department of Pediatrics, Division of Medical Genetics, Lucile Packard Children's Hospital, Stanford University, Stanford, California, USA.
² Department of Pediatrics, Division of Medical Genetics, Duke University, Durham, North Carolina, USA.
³ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
⁴ Department of Human Genetics, Division of Medical Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
⁵ Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
⁶ Epilepsy Centre Kork, Kehl, Germany.
⁷ Division of Pediatric Neurology, Department of Pediatrics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, Delaware, USA.
⁸ Division of Developmental Medicine, Department of Pediatrics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, Delaware, USA.
⁹ Department of Medicine, Imperial College, London, UK.
¹⁰ Department of Pathology and Laboratory Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
¹¹ 1] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA [2] Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA.
¹² Department of Genetics, Stanford University, Stanford, California, USA.
¹³ Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
¹⁴ Department of Pathology, Stanford University, Stanford, California, USA.
¹⁵ Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
¹⁶ 1] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA [2] Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA [3] Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas, USA.
¹⁷ 1] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA [2] Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
¹⁸ 1] Center for Human Genome Variation and Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA [2] Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA.

PMID: 24651605
PMCID: PMC4243708
DOI: 10.1038/gim.2014.22

Case Reports

Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway

Gregory M Enns et al. Genet Med. 2014 Oct.

. 2014 Oct;16(10):751-8.

doi: 10.1038/gim.2014.22. Epub 2014 Mar 20.

Authors

Collaborators

FORGE Canada Consortium:
Kym Boycott, Jan Friedman, Jacques Michaud, Francois Bernier, Michael Brudno, Bridget Fernandez, Bartha Knoppers, Mark Samuels, Steve Scherer

Affiliations

¹ Department of Pediatrics, Division of Medical Genetics, Lucile Packard Children's Hospital, Stanford University, Stanford, California, USA.
² Department of Pediatrics, Division of Medical Genetics, Duke University, Durham, North Carolina, USA.
³ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
⁴ Department of Human Genetics, Division of Medical Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
⁵ Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
⁶ Epilepsy Centre Kork, Kehl, Germany.
⁷ Division of Pediatric Neurology, Department of Pediatrics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, Delaware, USA.
⁸ Division of Developmental Medicine, Department of Pediatrics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, Delaware, USA.
⁹ Department of Medicine, Imperial College, London, UK.
¹⁰ Department of Pathology and Laboratory Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
¹¹ 1] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA [2] Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA.
¹² Department of Genetics, Stanford University, Stanford, California, USA.
¹³ Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
¹⁴ Department of Pathology, Stanford University, Stanford, California, USA.
¹⁵ Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
¹⁶ 1] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA [2] Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA [3] Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas, USA.
¹⁷ 1] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA [2] Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
¹⁸ 1] Center for Human Genome Variation and Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA [2] Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA.

PMID: 24651605
PMCID: PMC4243708
DOI: 10.1038/gim.2014.22

Erratum in

Genet Med. 2014 Jul;16(7):568. Chen, Rui [added]

Abstract

Purpose: The endoplasmic reticulum-associated degradation pathway is responsible for the translocation of misfolded proteins across the endoplasmic reticulum membrane into the cytosol for subsequent degradation by the proteasome. To define the phenotype associated with a novel inherited disorder of cytosolic endoplasmic reticulum-associated degradation pathway dysfunction, we studied a series of eight patients with deficiency of N-glycanase 1.

Methods: Whole-genome, whole-exome, or standard Sanger sequencing techniques were employed. Retrospective chart reviews were performed in order to obtain clinical data.

Results: All patients had global developmental delay, a movement disorder, and hypotonia. Other common findings included hypolacrima or alacrima (7/8), elevated liver transaminases (6/7), microcephaly (6/8), diminished reflexes (6/8), hepatocyte cytoplasmic storage material or vacuolization (5/6), and seizures (4/8). The nonsense mutation c.1201A>T (p.R401X) was the most common deleterious allele.

Conclusion: NGLY1 deficiency is a novel autosomal recessive disorder of the endoplasmic reticulum-associated degradation pathway associated with neurological dysfunction, abnormal tear production, and liver disease. The majority of patients detected to date carry a specific nonsense mutation that appears to be associated with severe disease. The phenotypic spectrum is likely to enlarge as cases with a broader range of mutations are detected.

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Conflict of interest statement

Conflicts of Interest

The authors declare no conflict of interest.

Figures

**Figure 1**
Relative frequency of clinical findings in NGLY1 deficiency.

**Figure 2**
Pedigrees of NGLY1-deficienct patients.

See this image and copyright information in PMC

Comment in

The shifting model in clinical diagnostics: how next-generation sequencing and families are altering the way rare diseases are discovered, studied, and treated.
Might M, Wilsey M. Might M, et al. Genet Med. 2014 Oct;16(10):736-7. doi: 10.1038/gim.2014.23. Epub 2014 Mar 20. Genet Med. 2014. PMID: 24651604 No abstract available.

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Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway

Collaborators

Affiliations

Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway

Authors

Collaborators

Affiliations

Erratum in

Abstract

Conflict of interest statement

Figures

Comment in

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Molecular Biology Databases

Research Materials