IMAGe syndrome (intrauterine growth restriction, metaphyseal dysplasia, adrenal 
hypoplasia congenita and genital anomalies) is an undergrowth developmental 
disorder with life-threatening consequences. An identity-by-descent analysis in 
a family with IMAGe syndrome identified a 17.2-Mb locus on chromosome 11p15 that 
segregated in the affected family members. Targeted exon array capture of the 
disease locus, followed by high-throughput genomic sequencing and validation by 
dideoxy sequencing, identified missense mutations in the imprinted gene CDKN1C 
(also known as P57KIP2) in two familial and four unrelated patients. A familial 
analysis showed an imprinted mode of inheritance in which only maternal 
transmission of the mutation resulted in IMAGe syndrome. CDKN1C inhibits 
cell-cycle progression, and we found that targeted expression of 
IMAGe-associated CDKN1C mutations in Drosophila caused severe eye growth defects 
compared to wild-type CDKN1C, suggesting a gain-of-function mechanism. All 
IMAGe-associated mutations clustered in the PCNA-binding domain of CDKN1C and 
resulted in loss of PCNA binding, distinguishing them from the mutations of 
CDKN1C that cause Beckwith-Wiedemann syndrome, an overgrowth syndrome.