ArticleThe Journal of clinical endocrinology and metabolism2014
A novel variant in CDKN1C is associated with intrauterine growth restriction, short stature, and early-adulthood-onset diabetes.
Article in The Journal of clinical endocrinology and metabolism, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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29 citing papers in PubMed, 66 citations in OpenAlex.
- Silver-Russell syndrome secondary to rare (epi)genotypes exhibits phenotypic heterogeneity challenging clinical diagnosis.Clinical epigenetics · 2025Article
- Identification of type 2 diabetes- and obesity-associated human β-cells using deep transfer learning.eLife · 2025Article
- Type 2 Diabetes in a Patient With IMAGe Syndrome Secondary to Polymerase Epsilon Pathogenic Variants.JCEM case reports · 2025Article
- Abundant Parent-of-origin Effect eQTL: The Framingham Heart Study.bioRxiv : the preprint server for biology · 2025Article
- Approach to the Patient With Suspected Silver-Russell Syndrome.The Journal of clinical endocrinology and metabolism · 2024Review
- Type 1 Diabetes in a Pediatric Patient With Beckwith-Wiedemann Syndrome.JCEM case reports · 2024Article
- Microcephaly GeneInternational journal of molecular sciences · 2024Article
- Article
- Monogenic diabetes.Nature reviews. Disease primers · 2023Review
- Divergent metabolic phenotypes in two genetic syndromes of low insulin secretion.Diabetes research and clinical practice · 2023Article
- Ongoing Challenges in the Diagnosis of 11p15.5-Associated Imprinting Disorders.Molecular diagnosis & therapy · 2022Article
- Deep exploration of aJournal of medical genetics · 2022Article
- Therapeutic advances in overcoming intrauterine growth restriction induced metabolic syndrome.Frontiers in pediatrics · 2022Review
- Genetic causes of growth hormone insensitivity beyond GHR.Reviews in endocrine & metabolic disorders · 2021Review
- Imprinted Genes Impact Upon Beta Cell Function in the Current (and Potentially Next) Generation.Frontiers in endocrinology · 2021Review
- Novel Variant inGenes · 2020Article
- Novel mutation points to a hot spot in CDKN1C causing Silver-Russell syndrome.Clinical epigenetics · 2020Article
- Functional Versatility of the CDK Inhibitor p57Frontiers in cell and developmental biology · 2020Review
- Primary adrenal insufficiency: New genetic causes and their long-term consequences.Clinical endocrinology · 2020Review
- Complex Phenotypes: Mechanisms Underlying Variation in Human Stature.Current osteoporosis reports · 2019Review
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Authors and funding
14 authors at 7 institutions in 3 countries.
Funding
Abstract
contextCDKN1C, 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.
objectiveTo investigate the genetic basis for a familial disorder characterized by intrauterine growth restriction, short stature, and early-adulthood-onset diabetes. DESIGN, SETTING, AND
participantsGenomic 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. 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.
resultsThe 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.
conclusionsWe report a novel CDKN1C mutation associated with features of IMAGe syndrome, but without adrenal insufficiency or metaphyseal dysplasia, and characterized by early-adulthood-onset 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.
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