A novel variant in CDKN1C is associated with intrauterine growth restriction, short stature, and early-adulthood-onset diabetes

Design, Setting, and Participants: Genomic DNA samples (15 affected and 26 unaffected from a six-generation pedigree) were analyzed by genome-wide single nucleotide polymorphism arrays, whole exome and Sanger sequencing, and multiplex ligation-dependent probe amplification.

Context: CDKN1C, a cyclin-dependent kinase inhibitor and negative regulator of cellular proliferation, is paternally imprinted and has been shown to regulate β-cell proliferation. CDKN1C mutations are associated with growth disorders, including Beckwith-Wiedemann syndrome and IMAGe syndrome.

Objective: To investigate the genetic basis for a familial disorder characterized by intrauterine growth restriction, short stature, and early-adulthood-onset diabetes.

Main Outcome Measure(s): Subjects were assessed for height, weight, adrenal gland size, ACTH, diabetes status, and testis volume. Linkage and sequence analyses were performed, and the identified genetic variant was functionally evaluated in reconstitution studies.

Results: The pedigree followed a paternally imprinted pattern of inheritance, and genetic linkage analysis identified a single significant 2.6-megabase locus on chromosome 11p15, within the imprinting center region 2. Multiplex ligation-dependent probe amplification did not detect copy number variants or methylation abnormalities. Whole exome sequencing revealed a single novel variant in the proliferating cell nuclear antigen-binding region of CDKN1C (c.842G>T, p.R281I) that co-segregated with affected status and, unlike variants found in IMAGe, did not entirely abrogate proliferating cell nuclear antigen binding. Clinical assessments revealed that affected individuals had low testicular volume but normal adrenal function.

Conclusions: We report a novel CDKN1C mutation associated with features of IMAGe syndrome, but without adrenal insufficiency or metaphyseal dysplasia, and characterized by early-adulthoodonset diabetes. Our data expand the range of phenotypes observed with CDKN1C defects and suggest that CDKN1C mutations may represent a novel monogenic form of diabetes.