Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome

Arboleda, Valerie A.; Lee, Hane; Parnaik, Rahul; Fleming, Alice; Banerjee, Abhik; Ferraz-de-Souza, Bruno; Délot, Emmanuèle C.; Rodriguez‐Fernandez, Imilce A.; Braslavsky, Débora; Bergadá, Ignacio; Dell’Angelica, Esteban C.; Nelson, Stanley F.; Martinez‐Agosto, Julian A.; Achermann, John C.; Vilain, Éric

doi:10.1038/ng.2275

Cited by 176 publications

(225 citation statements)

References 36 publications

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“…Other genetic causes include uniparental (maternal) disomy of chromosome 7 (UPD7) (79) and a mutation in the paternally imprinted gene CDKN1C (222). CDKN1C mutations are also associated with the IMAGe syndrome, characterized by intrauterine growth restriction, metaphyseal dysplasia, congenital adrenal hypoplasia, and genital anomalies (223), and a syndrome of pre and postnatal growth failure and early-onset diabetes mellitus (224). The clinical spectrum of Silver-Russell syndrome is considerably broader than thought before, and lack of intrauterine growth restriction should not automatically result in exclusion from molecular testing (225).…”

Section: Imprinting Disorders and Uniparental Disomymentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

Wit

Oostdijk

Losekoot

et al. 2016

European Journal of Endocrinology

141

132

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The fast technological development, particularly single nucleotide polymorphism array, array-comparative genomic hybridization, and whole exome sequencing, has led to the discovery of many novel genetic causes of growth failure. In this review we discuss a selection of these, according to a diagnostic classification centred on the epiphyseal growth plate. We successively discuss disorders in hormone signalling, paracrine factors, matrix molecules, intracellular pathways, and fundamental cellular processes, followed by chromosomal aberrations including copy number variants (CNVs) and imprinting disorders associated with short stature. Many novel causes of GH deficiency (GHD) as part of combined pituitary hormone deficiency have been uncovered. The most frequent genetic causes of isolated GHD are GH1 and GHRHR defects, but several novel causes have recently been found, such as GHSR, RNPC3, and IFT172 mutations. Besides well-defined causes of GH insensitivity (GHR, STAT5B, IGFALS, IGF1 defects), disorders of NFkB signalling, STAT3 and IGF2 have recently been discovered. Heterozygous IGF1R defects are a relatively frequent cause of prenatal and postnatal growth retardation. TRHA mutations cause a syndromic form of short stature with elevated T 3 /T 4 ratio. Disorders of signalling of various paracrine factors (FGFs, BMPs, WNTs, PTHrP/IHH, and CNP/NPR2) or genetic defects affecting cartilage extracellular matrix usually cause disproportionate short stature. Heterozygous NPR2 or SHOX defects may be found in w3% of short children, and also rasopathies (e.g., Noonan syndrome) can be found in children without clear syndromic appearance. Numerous other syndromes associated with short stature are caused by genetic defects in fundamental cellular processes, chromosomal abnormalities, CNVs, and imprinting disorders.

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Section: Imprinting Disorders and Uniparental Disomymentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

Wit

Oostdijk

Losekoot

et al. 2016

European Journal of Endocrinology

141

132

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“…Loss-of-function CDKN1C mutations are well known to be associated with BWS, but the first gain-of-function variants have been identified in patients with IMAGe syndrome (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, genitourinary abnormalities) [40] and later in SRS [20]. This finding was remarkable in at least three different ways: (a) functionally, the opposite phenotypic outcomes of BWS vs. IMAGe/SRS could be explained by the opposite functional properties of the mutations (for review: [41]); (b) gain-of-function mutations cause growth restriction only in maternal inheritance, because CDKN1C is expressed only from the maternal allele, and therefore IMAGe syndrome can be regarded as an ID; (c) CDKN1C also illustrated the limitations of NGS.…”

Section: Identification Of Cdkn1c Mutations As Monogenetic Causes Of mentioning

confidence: 99%

“…This finding was remarkable in at least three different ways: (a) functionally, the opposite phenotypic outcomes of BWS vs. IMAGe/SRS could be explained by the opposite functional properties of the mutations (for review: [41]); (b) gain-of-function mutations cause growth restriction only in maternal inheritance, because CDKN1C is expressed only from the maternal allele, and therefore IMAGe syndrome can be regarded as an ID; (c) CDKN1C also illustrated the limitations of NGS. Due to its high GC content, the NGS coverage for CDKN1C was much lower than for other genomic regions, and was only identified after its sequence was reanalyzed with the Sanger method [40], and furthermore, the bioinformatics analysis had to be adapted to a pedigree model with an influence of the parent-of-origin of putative mutations.…”

Section: Identification Of Cdkn1c Mutations As Monogenetic Causes Of mentioning

confidence: 99%

Congenital imprinting disorders: Application of multilocus and high throughput methods to decipher new pathomechanisms and improve their management

Soellner

Monk

Rezwan

et al. 2015

Molecular and Cellular Probes

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Imprinting disorders (IDs) are a group of congenital diseases affecting growth, development and metabolism. They are caused by changes in the allele-specific regulation ("epigenetic mutation") or in the genomic sequence ("genetic mutation") of imprinted genes. Currently molecular tests in ID patients are generally restricted to single loci classically associated with the disease, but this approach limits diagnostic yield, because of the molecular and clinical heterogeneity between IDs. From the technical point of view, these limitations are aggravated by the lack of standardization in testing methodology, in the DNA sequences tested, and in clinical inclusion criteria prompting testing.However, an increasing number of new studies show that these problems can be addressed by the use of new tests targeting multiple loci and/or a total exome and genome analysis.The rapid development of efficient and high-throughput molecular techniques and their applications in research and diagnostics in the last decade have led to an impressive increase of knowledge on IDs and their basic pathomechanisms. In combination with the improvement of data recording and documentation, the diagnostic strategies are increasingly based on standardized protocols, and thereby provide the backbone for directed counselling, more personalized management, and new therapeutic approaches.

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“…Gain of function of CDKN1C seems to be a major cause of restricted growth, as also suggested by the recent report of gain-of-function mutations in patients with IMAGe syndrome, a condition strikingly similar to SRS, characterized by growth retardation, skeletal dysplasia, adrenal hypoplasia and genital anomalies. 11,12 Because of the severity of LQT clinical presentation in the proposita with respect to the asymptomatic LQT in her mother, we speculated that this might be due to additional mutations either in the paternally inherited KCNQ1 allele or in other genes known to cause LQT. The sequence analysis of these genes did not detect pathogenic mutations, thus disclaiming this hypothesis.…”

Section: Resultsmentioning

confidence: 99%

Mild Beckwith-Wiedemann and severe long-QT syndrome due to deletion of the imprinting center 2 on chromosome 11p

Gurrieri

Zollino

Oliva³

et al. 2013

Eur J Hum Genet

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We report on a young woman admitted to our Cardiology Unit because of an episode of cardiac arrest related to a long-QT syndrome (LQTS). This manifestation was part of a broader phenotype, which was recognized as a mild form of BeckwithWiedemann syndrome (BWS). Molecular analysis confirmed the diagnosis of BWS owing to a maternally inherited deletion of the centromeric imprinting center, or ICR2, an extremely rare genetic mechanism in BWS. The deletion interval (198 kb) also included exons 11-16 of the KCNQ1 gene, known to be responsible for LQTS at locus LQT1. No concomitant mutations were found in any other of the known LQT genes. The proposita's mother carries the same deletion in her paternal chromosome and shows manifestations of the Silver-Russell syndrome (SRS). This report describes the smallest BWS-causing ICR2 deletion and provides the first evidence that a paternal deletion of ICR2 leads to a SRS-like phenotype. In addition, our observation strongly suggests that in cases of LQTS due to mutation of the KCNQ1 gene (LQT1), an accurate clinical genetic evaluation should be done in order to program the most appropriate genetic tests.

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Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome

Cited by 176 publications

References 36 publications

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

Congenital imprinting disorders: Application of multilocus and high throughput methods to decipher new pathomechanisms and improve their management

Mild Beckwith-Wiedemann and severe long-QT syndrome due to deletion of the imprinting center 2 on chromosome 11p

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