Discordant expression of a new WT1 gene mutation in a family with monozygotic twins presenting with congenital nephrotic syndrome

Abstract

Congenital nephrotic syndrome (CNS) is a heterogeneous group of diseases with different causes and prognoses. Two thirds of cases of NS in the first year of life are caused by mutations in four genes (NPHS1, NPHS2, WT1, and LAMB2). The mutation of WT1 gene can lead to Denys-Drash syndrome (DDS). We report on female monozygotic twins with CNS presenting at 7 and 8 weeks of age with anuric renal failure. Both twins were treated by peritoneal dialysis. Renal biopsy proved diffuse mesangial sclerosis. Genetic analysis detected a new heterozygote WT1 mutation R434P in both twins. One child developed a unilateral nephroblastoma. Both twins died because of complications of CNS (sepsis and extensive thrombosis of central venous system/sepsis and sudden heart failure) at ages 23 weeks/13.5 months, respectively. DNA analysis showed the same WT1 mutation in the father, who showed at his age of 41 years no clinical consequences of this mutation and no signs of DDS. In conclusion, we report the third family with monozygotic twins with DDS due to WT1 mutation. The DDS has very rapidly led to end-stage renal failure and death in both twins which is in striking contrast to the manifestation in their father.

Denys-Drash syndrome associated WT1 glutamine 369 mutants have altered sequence-preferences and altered responses to epigenetic modifications

“…Wilms tumors can arise from mutations in a number of different genes (14,15), but WT1-derived Wilms tumors, DDS, and FS all stem from mutations in the same, Wt1 , gene. The resulting phenotypes correlate well with the position and type of mutation present, although there are individual differences in the extents to which these are manifest, and overlaps in diagnoses (8,9,16). …”

Genotype–phenotype associations in WT1 glomerulopathy

“…Seventeen cases evaluated in this study had been included in previous publications. 3,[12][13][14][15][16][17][18][19][20][21][22] Statistics Statistical analyses were performed using Statistica 9.1 (StatSoft, Tulsa, OK) and SAS 9.2 (Cary, NC). The frequencies were compared using w 2 tests with adequate corrections and the Fisher exact probability test with Freeman-Halton extension for 2Â3 and 2Â4 tables when applicable.…”

Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease

“…Although the vast majority of such monozygotic twin pairs have been found to be concordant in terms of their clinical phenotypes (e.g. Miesfeldt et al 1998; Munhoz et al 2008; McDade et al 2012), others are quite discordant (Matsuo et al 2000; Amann et al 2001; Martin et al 2003; Holmgren et al 2004; Lachmann et al 2004; Czlonkowska et al 2009; Biegstraaten et al 2011; Fencl et al 2012; Iatropoulos et al 2012), suggesting that the environment can often play an important role in determining both the penetrance and expressivity of pathological mutations. [It should be borne in mind that there are various alternative genetic explanations for discordant phenotypes in monozygotic twins, including de novo post-zygotic mutation (Kentsis et al 2009; Vogt et al 2011), compensatory mutations (Mankad et al 2006) and somatic copy number variation (Bruder et al 2008) that obviate the need for a major contribution from the environment, as well as acquired epigenetic differences (Galetzka et al 2012; Bennett et al 2008)].…”