Wolcott-Rallison Syndrome is the most common genetic cause of permanent neonatal diabetes in consanguineous families

Rubio-Cabezas, Oscar, Patch, Ann-Marie, Minton, Jayne A. L., Flanagan, Sarah E., Edghill, Emma L., Hussain, Khalid, Balafrej, Amina, Deeb, Asma, Buchanan, Charles R., Jefferson, Ian G., Mutair, Angham, The Neonatal Diabetes International Collaborative Group, Hattersley, Andrew T. and Ellard, Sian (2009) Wolcott-Rallison Syndrome is the most common genetic cause of permanent neonatal diabetes in consanguineous families. The Journal of Clinical Endocrinology and Metabolism, 94 11: 4162-4170. doi:10.1210/jc.2009-1137


Author Rubio-Cabezas, Oscar
Patch, Ann-Marie
Minton, Jayne A. L.
Flanagan, Sarah E.
Edghill, Emma L.
Hussain, Khalid
Balafrej, Amina
Deeb, Asma
Buchanan, Charles R.
Jefferson, Ian G.
Mutair, Angham
The Neonatal Diabetes International Collaborative Group
Hattersley, Andrew T.
Ellard, Sian
Title Wolcott-Rallison Syndrome is the most common genetic cause of permanent neonatal diabetes in consanguineous families
Journal name The Journal of Clinical Endocrinology and Metabolism   Check publisher's open access policy
ISSN 0021-972X
Publication date 2009-11-01
Sub-type Article (original research)
DOI 10.1210/jc.2009-1137
Volume 94
Issue 11
Start page 4162
End page 4170
Total pages 9
Place of publication United States
Publisher The Endocrine Society
Language eng
Formatted abstract
Context and Objective:
Mutations in EIF2AK3 cause Wolcott-Rallison syndrome (WRS), a rare recessive disorder characterized by early-onset diabetes, skeletal abnormalities, and liver dysfunction. Although early diagnosis is important for clinical management, genetic testing is generally performed after the full clinical picture develops. We aimed to identify patients with WRS before any other abnormalities apart from diabetes are present and study the overall frequency of WRS among patients with permanent neonatal diabetes.

Research Design and Methods:

The coding regions of EIF2AK3 were sequenced in 34 probands with infancy-onset diabetes with a clinical phenotype suggestive of WRS (n = 28) or homozygosity at the WRS locus (n = 6).

Results:
Twenty-five probands (73.5%) were homozygous or compound heterozygous for mutations in EIF2AK3. Twenty of the 26 mutations identified were novel. Whereas a diagnosis of WRS was suspected before genetic testing in 22 probands, three patients with apparently isolated diabetes were diagnosed after identifying a large homozygous region encompassing EIF2AK3. In contrast to nonconsanguineous pedigrees, mutations in EIF2AK3 are the most common known genetic cause of diabetes among patients born to consanguineous parents (24 vs. < 2%). Age at diabetes onset and birth weight might be used to prioritize genetic testing in the latter group.

Conclusions:

WRS is the most common cause of permanent neonatal diabetes mellitus in consanguineous pedigrees. In addition to testing patients with a definite clinical diagnosis, EIF2AK3 should be tested in patients with isolated neonatal diabetes diagnosed after 3 wk of age from known consanguineous families, isolated populations, or countries in which inbreeding is frequent. Copyright © 2009 by The Endocrine Society.
Keyword Translational control
Activating mutations
INS gene
Mellitus
Insulin
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
 
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Created: Thu, 05 May 2011, 21:41:47 EST by Susan Allen on behalf of Institute for Molecular Bioscience