Recurrent reciprocal genomic rearrangements of 17q12 are associated with renal disease, diabetes, and epilepsy.
Most studies of genomic disorders have focused on patients with cognitive disability and/or peripheral nervous system defects. In an effort to broaden the phenotypic spectrum of this disease model, we assessed 155 autopsy samples from fetuses with well-defined developmental pathologies in regions predisposed to recurrent rearrangement, by array-based comparative genomic hybridization. We found that 6% of fetal material showed evidence of microdeletion or microduplication, including three independent events that likely resulted from unequal crossing-over between segmental duplications. One of the microdeletions, identified in a fetus with multicystic dysplastic kidneys, encompasses the TCF2 gene on 17q12, previously shown to be mutated in maturity-onset diabetes, as well as in a subset of pediatric renal abnormalities. Fine-scale mapping of the breakpoints in different patient cohorts revealed a recurrent 1.5-Mb de novo deletion in individuals with phenotypes that ranged from congenital renal abnormalities to maturity-onset diabetes of the young type 5. We also identified the reciprocal duplication, which appears to be enriched in samples from patients with epilepsy. We describe the first example of a recurrent genomic disorder associated with diabetes.
Mefford
Heather C
HC
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
Clauin
Severine
S
Sharp
Andrew J
AJ
Moller
Rikke S
RS
Ullmann
Reinhard
R
Kapur
Raj
R
Pinkel
Dan
D
Cooper
Gregory M
GM
Ventura
Mario
M
Ropers
H Hilger
HH
Tommerup
Niels
N
Eichler
Evan E
EE
Bellanne-Chantelot
Christine
C
D000328:Adult; D000368:Aged; D001344:Autopsy; D002872:Chromosome Deletion; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D003920:Diabetes Mellitus / Q000235:genetics*; D004827:Epilepsy / Q000150:complications / Q000235:genetics*; D005260:Female; D005333:Fetus / Q000002:abnormalities; D018628:Gene Dosage; D020440:Gene Duplication; D015321:Gene Rearrangement / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D007674:Kidney Diseases / Q000150:complications / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009693:Nucleic Acid Hybridization; D010375:Pedigree; D010641:Phenotype