ABSTRACT
FOG-2 (Friend of GATA 2) is a transcriptional cofactor able to differentially regulate the expression of GATA-target genes in different promoter contexts. Mouse models evidenced that FOG-2 plays a role in congenital heart disease and normal testis development. In human, while FOG-2 mutations have been identified in sporadic cases of tetralogy of Fallot, no mutations are described to be associated with impaired gonadal function. We here describe a young boy with a balanced t(8;10)(q23.1;q21.1) translocation who was born with congenital secundum-type atrial septal defect and gonadal dysgenesis. Fluorescence in situ hybridization mapped the chromosome 8 translocation breakpoint (bkp) to within the IVS4 of the FOG-2 gene, whereas the chromosome 10 bkp was found to lie in a desert gene region. Quantitative analysis of FOG-2 expression revealed the presence of a truncated transcript but there was no detectable change in the expression of the genes flanking the 10q bkp, thus making it possible to assign the observed clinical phenotype to altered FOG-2 expression. Genetic and clinical analyses provide insights into the signaling pathways by which FOG-2 affects not only cardiac development but also gonadal function and its preservation.
Subject(s)
Chromosomes, Human, Pair 10 , Chromosomes, Human, Pair 8 , DNA-Binding Proteins/genetics , Gonadal Dysgenesis/genetics , Heart Septal Defects, Atrial/genetics , Transcription Factors/genetics , Translocation, Genetic , Amino Acid Sequence , Child , DNA-Binding Proteins/chemistry , Humans , Karyotyping , Male , Sequence Deletion , Transcription Factors/chemistryABSTRACT
BACKGROUND: Beckwith-Wiedemann syndrome (BWS) is an overgrowth disorder with increased risk of paediatric tumours. The aetiology involves epigenetic and genetic alterations affecting the 11p15 region, methylation of the differentially methylated DMR2 region being the most common defect, while less frequent aetiologies include mosaic paternal 11p uniparental disomy (11patUPD), maternally inherited mutations of the CDKN1C gene, and hypermethylation of DMR1. A few patients have cytogenetic abnormalities involving 11p15.5. METHODS: Screening of 70 trios of BWS probands for 11p mosaic paternal UPD and for cryptic cytogenetic rearrangements using microsatellite segregation analysis identified a profile compatible with paternal 11p15 duplication in two patients. RESULTS: Fluorescence in situ hybridisation analysis revealed in one case the unbalanced translocation der(21)t(11;21)(p15.4;q22.3) originated from missegregation of a cryptic paternal balanced translocation. The second patient, trisomic for D11S1318, carried a small de novo dup(11)(p15.5p15.5), resulting from unequal recombination at paternal meiosis I. The duplicated region involves only IC1 and spares IC2/LIT1, as shown by fluorescent in situ hybridisation (FISH) mapping of the proximal duplication breakpoint within the amino-terminal part of KvLQT1. CONCLUSIONS: An additional patient with Wolf-Hirschorn syndrome was shown by FISH studies to carry a der(4)t(4;11)(p16.3;p15.4), contributed by a balanced translocation father. Interestingly, refined breakpoint mapping on 11p and the critical regions on the partner 21q and 4p chromosomal regions suggested that both translocations affecting 11p15.4 are mediated by segmental duplications. These findings of chromosomal rearrangements affecting 11p15.5-15.4 provide a tool to further dissect the genomics of the BWS region and the pathogenesis of this imprinting disorder.
