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


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.
Rubio-Cabezas
Oscar
O
Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter EX2 5DW, United Kingdom.
Patch
Ann-Marie
AM
Minton
Jayne A L
JA
Flanagan
Sarah E
SE
Edghill
Emma L
EL
Hussain
Khalid
K
Balafrej
Amina
A
Deeb
Asma
A
Buchanan
Charles R
CR
Jefferson
Ian G
IG
Mutair
Angham
A
Hattersley
Andrew T
AT
Ellard
Sian
S
D017668:Age of Onset; D000013:Congenital Abnormalities / Q000235:genetics*; D003241:Consanguinity; D004247:DNA / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D003920:Diabetes Mellitus / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D030342:Genetic Diseases, Inborn / Q000235:genetics; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D008099:Liver / Q000503:physiopathology; D008297:Male; D009154:Mutation; D016133:Polymerase Chain Reaction; D013577:Syndrome; D019892:eIF-2 Kinase / Q000235:genetics*
D004247:DNA; C460640:EIF2AK3 protein, human; D019892:eIF-2 Kinase