RESUMEN
Beckwith-Wiedemann syndrome (BWS) is a phenotypically and genotypically heterogeneous overgrowth syndrome characterized by somatic overgrowth, macroglossia and abdominal wall defects. Other usual findings are hemihyperplasia, embryonal tumours, adrenocortical cytomegaly, ear anomalies, visceromegaly, renal abnormalities, neonatal hypoglycaemia, cleft palate, polydactyly and a positive family history. BWS is a complex, multigenic disorder associated, in up to 90% of patients, with alteration in the expression or function of one or more genes in the 11p15.5 imprinted gene cluster. There are several molecular anomalies associated with BWS and the large proportion of cases, about 85%, is sporadic and karyotypically normal. One of the major categories of BWS molecular alteration (10-20% of cases) is represented by mosaic paternal uniparental disomy (pUPD), namely patients with two paternally derived copies of chromosome 11p15 and no maternal contribution for that. In these patients, in addition to the effects of IGF2 overexpression, a decreased level of the maternally expressed gene CDKN1C may contribute to the BWS phenotype. In this paper, we reviewed a series of nine patients with BWS because of pUPD using several methods with the aim to evaluate the percentage of mosaicism, the methylation status at both loci, the extension of the pUPD at the short arm and the breakpoints of recombination. Fine mapping of mitotic recombination breakpoints by single-nucleotide polymorphism-array in individuals with UPD and fine estimation of epigenetic defects will provide a basis for understanding the aetiology of BWS, allowing more accurate prognostic predictions and facilitating management and surveillance of individuals with this disorder.
Asunto(s)
Síndrome de Beckwith-Wiedemann/genética , Disomía Uniparental/citología , Puntos de Rotura del Cromosoma , Mapeo Cromosómico/métodos , Cromosomas Humanos Par 11/genética , Metilación de ADN/genética , Epigenómica , Impresión Genómica/genética , Humanos , Factor II del Crecimiento Similar a la Insulina/genética , Repeticiones de Microsatélite/genética , Mosaicismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Fenotipo , Análisis de Secuencia de ADN , Disomía Uniparental/genéticaRESUMEN
The ZIC genes comprise a family of transcriptional factors associated with neural tube defects (NTDs) in mice and with holoprosencephaly in humans. An allelic variant of ZIC2, a CAC repeat within the first exon, was reported in association with an increased risk of non-syndromic NTDs in patients with a Hispanic ethnic background. We investigated whether this 10-residue histidine tract polymorphism of the ZIC2 gene (c.718_720dupCAC) was associated with the risk of NTDs in a sample of 138 patients and their parents from the Latin American Collaborative Study of Congenital Malformations (ECLAMC) hospital network. Analysis with log-linear models of 138 family triads of mother, father and affected child did not provide evidence to support the notion that case (or maternal) 10H/10H or -/10H genotypes were associated with NTDs in this South American population sample, where the 10H variant occurred in 5% of newborns affected with NTDs. We also described the first example of the homozygous state of the 10H allele in a patient with cephalocele, holoprosencephaly and microphthalmia, but did not ascertain whether this polymorphism is associated with the increased risk of a specific subgroup of NTDs, as a normal father of a patient with anencephaly presented the same genotype.