Genome-wide loss of maternal alleles in a nephrogenic rest and Wilms' tumour from a BWS patient.
ABSTRACT A patient with Beckwith-Wiedemann syndrome (BWS) presented with Wilms' tumour. Examination of the nephrectomy specimen showed, in addition to the tumour, the presence of nephrogenic rests. Nephrogenic rests are thought to be precursor lesions from which a Wilms' tumour may develop. A molecular analysis examining the loss of constitutional heterozygosity (LOCH), initially for chromosome 11, was performed on peripheral blood, the normal kidney, nephrogenic rest and tumour material. The study was extended to include markers from all 23 chromosomes. At each informative, locus, LOCH of the maternal allele was shown in the nephrogenic rest and tumour material. In addition, the normal kidney displayed allele imbalance. It would appear from these results that either extensive LOCH across the genome was an early genetic event in the development of malignancy in this patient or that the tumour and rest developed from cells containing no maternal chromosomes. The apparent LOCH seen in the normal kidney sample implies that full reduction to homozygosity is consistent with a histologically normal appearance. Putative mechanisms to explain this phenomenon are discussed.
[Show abstract] [Hide abstract]
ABSTRACT: Genomic imprinting is an epigenetic phenomenon that leads to parent-specific differential expression of a subset of genes. Most imprinted genes form clusters, or imprinting domains, and are regulated by imprinting control regions. As imprinted genes have an important role in growth and development, aberrant expression of imprinted genes due to genetic or epigenetic abnormalities is involved in the pathogenesis of human disorders, or imprinting disorders. Beckwith-Wiedemann syndrome (BWS) is a representative imprinting disorder characterized by macrosomia, macroglossia and abdominal wall defects, and exhibits a predisposition to tumorigenesis. The relevant imprinted chromosomal region in BWS is 11p15.5, which consists of two imprinting domains, IGF2/H19 and CDKN1C/KCNQ1OT1. BWS has five known causative epigenetic and genetic alterations: loss of methylation (LOM) at KvDMR1, gain of methylation (GOM) at H19DMR, paternal uniparental disomy, CDKN1C mutations and chromosomal rearrangements. Opposite methylation defects, GOM and LOM, at H19DMR are known to cause clinically opposite disorders: BWS and Silver-Russell syndrome, respectively. Interestingly, a recent study discovered that loss of function or gain of function of CDKN1C also causes clinically opposite disorders, BWS and IMAGe (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies) syndrome, respectively. Furthermore, several clinical studies have suggested a relationship between assisted reproductive technology (ART) and the risk of imprinting disorders, along with the existence of trans-acting factors that regulate multiple imprinted differentially methylated regions. In this review, we describe the latest knowledge surrounding the imprinting mechanism of 11p15.5, in addition to epigenetic and genetic etiologies of BWS, associated childhood tumors, the effects of ART and multilocus hypomethylation disorders.Journal of Human Genetics advance online publication, 30 May 2013; doi:10.1038/jhg.2013.51.Journal of Human Genetics 05/2013; DOI:10.1038/jhg.2013.51 · 2.53 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Here we describe three subjects with mosaic genome-wide paternal uniparental isodisomy (GWpUPD) each of whom presented initially with overgrowth, hemihyperplasia (HH), and hyperinsulinism (HI). Due to the severity of findings and the presence of additional features, SNP array testing was performed, which demonstrated mosaic GWpUPD. Comparing these individuals to 10 other live-born subjects reported in the literature, the predominant phenotype is that of pUPD11 and notable for a very high incidence of tumor development. Our subjects developed non-metastatic tumors of the adrenal gland, kidney, and/or liver. All three subjects had pancreatic hyperplasia resulting in HI. Notably, our subjects to date display minimal features of other diseases associated with paternal UPD loci. Both children who survived the neonatal period have displayed near-normal cognitive development, likely due to a favorable tissue distribution of the mosaicism. To understand the range of UPD mosaicism levels, we studied multiple tissues using SNP array analysis and detected levels of 5-95%, roughly correlating with the extent of tissue involvement. Given the rapidity of tumor growth and the difficulty distinguishing malignant and benign tumors in these GWpUPD subjects, we have utilized increased frequency of ultrasound (US) and alpha-fetoprotein (AFP) screening in the first years of life. Because of a later age of onset of additional tumors, continued tumor surveillance into adolescence may need to be considered in these rare patients. © 2013 Wiley Periodicals, Inc.American Journal of Medical Genetics Part A 06/2013; DOI:10.1002/ajmg.a.36045 · 2.05 Impact Factor
Article: Genome Wide Androgenetic Mosaicism.[Show abstract] [Hide abstract]
ABSTRACT: BACKGROUND: Individuals with mosaic UPD of apparently all chromosomes have recently been described. They show a 46,XX karyotype, but with a mixture of normal biparental cells and cells entirely of paternal isodisomic origin. We describe an infant who primarily showed signs of Beckwith-Wiedemann syndrome (BWS), but also had other severe and eventually lethal medical problems, notably refractory hypoglycemia. METHODS: We performed methylation studies for BWS, but incidentally for Angelman syndrome (AS) on leukocytes and in a skin FFPE sample. We also performed chromosome microarray (CNV and SNP array) on leukocytes. RESULTS: We found that the patient had hypomethylation consistent with both BWS and AS. Remarkably, this was due to mosaic paternal UPD for chromosomes 11 and 15, respectively. The SNP microarray showed mosaic paternal UPD for all chromosomes. CONCLUSION: Patients with unusual phenotypes for a typical imprinting disorder should be studied further with assays for imprinted loci on other chromosomes. Chromosomal SNP microarrays are useful in identifying patients with multiple UPDs, sometimes of the whole genome.Clinical Genetics 03/2013; 85(3). DOI:10.1111/cge.12146 · 3.65 Impact Factor