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DDOST mutations identified by whole-exome sequencing are implicated in congenital disorders of glycosylation

Melanie A Jones1, Bobby G Ng, Shruti Bhide

  • 1Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.

American Journal of Human Genetics
|February 7, 2012
PubMed

Insights

Whole-exome sequencing combined with biochemical analysis identified DDOST gene mutations in an undiagnosed Congenital Disorders of Glycosylation (CDG) patient. This approach successfully pinpointed the genetic cause of N-glycosylation impairment in this rare inherited disease.

Area of Science:

  • Biochemistry
  • Genetics
  • Molecular Biology

Background:

  • Congenital Disorders of Glycosylation (CDG) are inherited diseases impairing N-glycosylation, often leading to severe organ dysfunction and early mortality.
  • Current diagnostic methods, like transferrin glycosylation analysis, identify affected individuals but do not provide a genetic diagnosis, leaving many cases undiagnosed.
  • A significant portion of patients with abnormal transferrin glycosylation lack mutations in known CDG genes, highlighting the need for novel diagnostic strategies.

Purpose of the Study:

  • To identify the genetic cause of N-glycosylation defects in a patient with undiagnosed Congenital Disorders of Glycosylation (CDG).
  • To demonstrate the utility of combining whole-exome sequencing (WES) with biochemical analyses for diagnosing rare genetic disorders.
  • To confirm the pathogenicity of identified genetic variants through functional studies.

Main Methods:

  • Whole-exome sequencing (WES) was employed to identify genetic variants in the patient.
  • Biochemical analyses, including assessment of three biomarkers, were performed on patient fibroblasts to evaluate N-glycosylation status.
  • A glyco-complementation system involving the introduction of wild-type DDOST cDNA was used to functionally validate the identified mutations.

Main Results:

  • WES identified a 22 bp deletion and a missense mutation in the DDOST gene, which encodes a component of the oligosaccharyltransferase complex.
  • Biochemical analysis confirmed reduced N-glycosylation in the patient's fibroblasts.
  • Complementation with wild-type DDOST cDNA restored normal glycosylation in patient fibroblasts, confirming the mutations' pathological role.

Conclusions:

  • The combined approach of WES and biochemical studies, including glyco-complementation, is powerful for identifying and confirming causative genes in undiagnosed CDG patients.
  • Mutations in DDOST were identified as the cause of N-glycosylation impairment in this patient.
  • This methodology holds significant promise for uncovering additional causative genes for various types of CDG, advancing the diagnosis and understanding of these complex disorders.

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