CDKN1C (p57^Kip2) analysis in Beckwith–Wiedemann syndrome (BWS) patients: Genotype–phenotype correlations, novel mutations, and polymorphisms

Abstract

Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome characterized by macroglossia, macrosomia, and abdominal wall defects. It is a multigenic disorder caused in most patients by alterations in growth regulatory genes. A small number of individuals with BWS (5-10%) have mutations in CDKN1C, a cyclin-dependent kinase inhibitor of G1 cyclin complexes that functions as a negative regulator of cellular growth and proliferation. Here, we report on eight patients with BWS and CDKN1C mutations and review previous reported cases. We analyzed 72 patients (50 BWS, 17 with isolated hemihyperplasia (IH), three with omphalocele, and two with macroglossia) for CDKN1C defects with the aim to search for new mutations and to define genotype-phenotype correlations. Our findings suggest that BWS patients with CDKN1C mutations have a different pattern of clinical malformations than those with other molecular defects. Polydactyly, genital abnormalities, extra nipple, and cleft palate are more frequently observed in BWS with mutations in CDKN1C. The clinical observation of these malformations may help to decide which genetic characterization should be undertaken (i.e., CDKN1C screening), thus optimizing the laboratory evaluation for BWS.

(Epi)genotype–phenotype correlations in Beckwith–Wiedemann syndrome

“…18 The presence of genome-wide UPD was tested in 28 UPD patients by microsatellite analysis and single-nucleotide polymorphism array. CDKN1C gene sequencing as described elsewhere 19 was carried out in 154 patients selected on the basis of negativity of methylation sensitive tests plus 2 of the above-mentioned BWS diagnostic criteria and either familiarity for BWS or signs/malformations highly specific for CDKN1C variants (as palatoschisis or omphalocele). 3 Pathogenicity prediction of CDKN1C variants was tested by the bioinformatic tools PolyPhen-2 (Polymorphism Phenotyping), SIFT (Sorting Intolerant From Tolerant), and PROVEAN (Protein Variation Effect Analyzer).…”

Prenatal molecular testing for Beckwith–Wiedemann and Silver–Russell syndromes: a challenge for molecular analysis and genetic counseling

“…During pregnancy, preeclampsia or eclampsia may occur. 35,36 Silver-Russell syndrome SRS is characterized by intrauterine and postnatal growth restriction with a typical facial gestalt (for a review, Saal 16 ). In the majority of patients, birth weight is 2-3 s.d.…”

Epigenetics and imprinting in human disease

“…Maternally-inherited loss of function mutations in CDKN1C are reported in about 10% of BWS patients and about 40% of familial cases of BWS . BWS patients with CDKN1C mutations are more likely to have polydactyly, genital abnormalities, cleft palate and are less likely to develop tumors compared with other molecular causes of BWS, suggesting that decreased CDKN1C expression disrupts development of these organ systems (Kantaputra et al, 2013, Romanelli et al, 2010. Activating mutations in CDKN1C have been reported in RSS patients (Azzi et al, 2014).…”