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

Sarah L. Kerns, Jaime Guevara-Aguirre, Shayne Andrew, Juan Geng, Carolina Guevara, Marco Guevara-Aguirre, Michael Guo, Carole Oddoux, Yiping Shen, Andres Zurita, Ron G. Rosenfeld, Harry Ostrer, Vivian Hwa, Andrew Dauber

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)E2117-E2122
JournalJournal of Clinical Endocrinology and Metabolism
Volume99
Issue number10
DOIs
StatePublished - Oct 1 2014

Fingerprint

Medical problems
Exome
Multiplex Polymerase Chain Reaction
Proliferating Cell Nuclear Antigen
Pedigree
Mutation
Growth
Cell Proliferation
Beckwith-Wiedemann Syndrome
Growth Disorders
Amplification
Inheritance Patterns
Adrenal Insufficiency
Genetic Linkage
Cyclin-Dependent Kinases
Adrenal Glands
Adrenocorticotropic Hormone
Methylation
Single Nucleotide Polymorphism
Sequence Analysis

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)

Cite this

A novel variant in CDKN1C is associated with intrauterine growth restriction, short stature, and early-adulthood-onset diabetes. / Kerns, Sarah L.; Guevara-Aguirre, Jaime; Andrew, Shayne; Geng, Juan; Guevara, Carolina; Guevara-Aguirre, Marco; Guo, Michael; Oddoux, Carole; Shen, Yiping; Zurita, Andres; Rosenfeld, Ron G.; Ostrer, Harry; Hwa, Vivian; Dauber, Andrew.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 99, No. 10, 01.10.2014, p. E2117-E2122.

Research output: Contribution to journalArticle

Kerns, SL, Guevara-Aguirre, J, Andrew, S, Geng, J, Guevara, C, Guevara-Aguirre, M, Guo, M, Oddoux, C, Shen, Y, Zurita, A, Rosenfeld, RG, Ostrer, H, Hwa, V & Dauber, A 2014, 'A novel variant in CDKN1C is associated with intrauterine growth restriction, short stature, and early-adulthood-onset diabetes', Journal of Clinical Endocrinology and Metabolism, vol. 99, no. 10, pp. E2117-E2122. https://doi.org/10.1210/jc.2014-1949
Kerns, Sarah L. ; Guevara-Aguirre, Jaime ; Andrew, Shayne ; Geng, Juan ; Guevara, Carolina ; Guevara-Aguirre, Marco ; Guo, Michael ; Oddoux, Carole ; Shen, Yiping ; Zurita, Andres ; Rosenfeld, Ron G. ; Ostrer, Harry ; Hwa, Vivian ; Dauber, Andrew. / A novel variant in CDKN1C is associated with intrauterine growth restriction, short stature, and early-adulthood-onset diabetes. In: Journal of Clinical Endocrinology and Metabolism. 2014 ; Vol. 99, No. 10. pp. E2117-E2122.
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abstract = "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.",
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AU - Kerns, Sarah L.

AU - Guevara-Aguirre, Jaime

AU - Andrew, Shayne

AU - Geng, Juan

AU - Guevara, Carolina

AU - Guevara-Aguirre, Marco

AU - Guo, Michael

AU - Oddoux, Carole

AU - Shen, Yiping

AU - Zurita, Andres

AU - Rosenfeld, Ron G.

AU - Ostrer, Harry

AU - Hwa, Vivian

AU - Dauber, Andrew

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N2 - 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.

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