Dissecting TSC2-mutated renal and hepatic angiomyolipomas in an individual with ARID1B-associated intellectual disability

Background Several subunits of the SWI/SNF chromatin remodeling complex are implicated in both cancer and neurodevelopmental disorders (NDD). Though there is no clinical evidence for an increased tumor risk in individuals with NDDs due to germline mutations in most of these genes so far, this has been repeatedly proposed and discussed. A young woman with NDD due to a de novo mutation in ARID1B now presented with a large renal (> 19 cm in diameter) and multiple hepatic angiomyolipomas (AMLs) but no other signs of tuberous sclerosis complex. Methods We analyzed tumor and healthy tissue samples with exome and panel sequencing. Results Additionally to the previously known, germline ARID1B variant we identified a post-zygotic truncating TSC2 variant in both renal and hepatic AMLs but not in any of the healthy tissues. We did not detect any further, obvious tumor driver events. The identification of a passenger variant in SIPA1L3 in both AMLs points to a common clonal origin. Metastasis of the renal AML into the liver is unlikely on the basis of discordant histopathological features. Our findings therefore point to very low-grade mosaicism for the TSC2 variant, possibly in a yet unknown mesenchymal precursor cell that expanded clonally during tumor development. A possible contribution of the germline ARID1B variant to the tumorigenesis remains unclear but cannot be excluded given the absence of any other evident tumor drivers in the AMLs. Conclusion This unique case highlights the blurred line between tumor genetics and post-zygotic events that can complicate exact molecular diagnoses in patients with rare manifestations. It also demonstrates the relevance of multiple disorders in a single individual, the challenges of detecting low-grade mosaicisms, and the importance of proper diagnosis for treatment and surveillance

Teken, landskap en kennis : 'n ondersoek na die rol van teken in Suid-Afrikaanse kuns

Thesis (MA)--Stellenbosch University, 2003.ENGLISH ABSTRACT: This thesis explores the role played by drawings in the creation of knowledge. The study specifically focuses on drawings of the South African landscape and how it led to knowledge of our country. The Western perception of the concept of nature in relation to culture or civilisation is investigated by brief reference to a few periods in Western history. It is argued that man and nature was separated in Western thought by the establishment of rational thinking. This concept led to man's exploitation of nature to his own advantage. The division between man and nature was broadened in the quest for technological advancement. The first European travellers came to South Africa with a Western mind set, hoping for better economical conditions. The illustrated traveller's report reflects the verbal and visual capturing and exploitation of the South African landscape. It is further argued that European travellers tried to structure the landscape according to Western aesthetical traditions. Drawings appear to be picturesque but have radical political, economical and social implications. Colonial depictions created knowledge, but in fact symbolically legitimise the expansion of power. Until the middle of the twentieth century Western aesthetic traditions were applied to visual depictions of the South African landscape. During this period, artists were uncritical of the oppressive political system and in doing so gave their tacit consent. Ever since the middle of the twentieth century, several artists voiced their opinions against the unfair policy of the ruling political party. Visual images asked subtle questions and gave radical judgements; thus knowledge was created and a contribution made to the freedom of all South Africans. My drawings of South African landscapes are to be understood against this theoretical background. I use drawings to ask questions about the relationship between the visual image and the establishment of knowledge. I also refer to the relationship between the original and the copy, reality, the photo and the drawing. I conclude the following: drawings lead to the creation of knowledge and landscape depictions have implications of power. The solution to this problem lies, in the end, once more III drawings.My depictions of South African landscapes are given as an answer.AFRIKAANSE OPSOMMING: Hierdie tesis is 'n ondersoek na die rol wat visuele beelde kan speel in die oordrag van idees. Daar word spesifiek gekyk na hoe tekeninge van die Suid-Afrikaanse landskap gelei het tot die totstandkoming van kennis oor ons land. Die Westerse verstaan van die begrip natuur in verhouding tot kultuur of beskawing word ondersoek deur kortliks te verwys na 'n paar periodes gedurende die Westerse geskiedenis. Daar word aangevoer dat Westerse denke die mens en die natuur van mekaar geskei het deur die instelling van rasionele denke. So het daar 'n geloof in menslike rede ontstaan. Dié beskouing het daartoe gelei dat die mens die natuur begin uitbuit het tot eie voordeel. Die kloof tussen mens en natuur het al hoe dieper geword in 'n strewe na tegnologiese vooruitgang. Die eerste Europese reisigers het vanuit 'n Westerse verwysingsraamwerk na Suid-Afrika gekom met die hoop op beter ekonomiese vooruitsigte. Die geïllustreerde reisverslag weerspieël die inneming en uitbuiting van die Suid-Afrikaanse landskap visueel en verbaal. Daar word aangevoer dat Europese reisigers die landskap deur middel van tekeninge, uitgevoer volgens Westerse estetiese tradisies, probeer struktureer het. Tekeninge kom skilderagtig voor, maar het radikale politiese, ekonomiese en sosiale implikasies. Koloniale tekeninge het kennis geskep en in werklikheid magsuitbreiding simbolies gelegitimeer. Westerse estetiese tradisies is tot die middel van die twintigste eeu toegepas op visuele uitbeeldings van die Suid-Afrikaanse landskap. Gedurende dié tydperk het kunstenaars die onderdrukkende, heersende politieke stelsel in werklikheid ondersteun deur totaalonkrities daarteenoor te staan. Teen die middel van die twintigste eeu het verskillende kunstenaars in opstand gekom teen die onregverdige beleid van die regerende party. Visuele beelde is gebruik om subtiele vrae te stel sowel as radikale uitsprake te lewer en het so kennis geskep en bygedra tot die bevryding van alle Suid- Afrikaners. My tekeninge van Suid-Afrikaanse landskappe moet teen dié teoretiese agtergrond gelees word. Ek gebruik teken om vrae steloor die verhouding tussen die visuele beeld en kennis wat so tot stand kom. Daar word verwys na die verhouding tussen oorspronklike en kopie, werklikheid, foto en tekening. Die gevolgtrekking is dat tekeninge kan lei tot die totstandkoming van kennis en dat uitbeeldings van landskappe magsimplikasies kan hê. Die oplossing vir hierdie probleem lê uiteindelik weer in tekeninge. My uitbeeldings van Suid-Afrikaanse landskappe word as antwoord gebied

Molecular diagnosis of kidney transplant failure based on urine

In light of the organ shortage, there is a great responsibility to assess postmortal organs for which procurement has been consented and to increase the life span of transplanted organs. The former responsibility has moved many centers to accept extended criteria organs. The latter responsibility requires an exact diagnosis and, if possible, omission of the harmful influence on the transplant. We report the course of a kidney transplant that showed a steady decline of function over a decade, displaying numerous cysts of different sizes. Clinical workup excluded the most frequent causes of chronic transplant failure. The filed allocation documents mentioned the donor’s disease of oral‐facial‐digital syndrome, a rare ciliopathy, which can also affect the kidney. Molecular diagnosis was performed by culturing donor tubular cells from the recipient´s urine more than 10 years after transplantation. Next‐generation panel sequencing with DNA from tubular urinary cells revealed a novel truncating mutation in OFD1, which sufficiently explains the features of the kidney transplants, also found in the second kidney allograft. Despite this severe donor disease, lifesaving transplantation with good long‐term outcome was enabled for 5 recipients

Prenatal diagnosis of HNF1B-associated renal cysts: Is there a need to differentiate intragenic variants from 17q12 microdeletion syndrome?

OBJECTIVE 17q12 microdeletions containing HNF1B and intragenic variants within this gene are associated with variable developmental, endocrine, and renal anomalies, often already noted prenatally as hyperechogenic/cystic kidneys. Here, we describe prenatal and postnatal phenotypes of seven individuals with HNF1B aberrations and compare their clinical and genetic data to those of previous studies. METHODS Prenatal sequencing and postnatal chromosomal microarray analysis were performed in seven individuals with renal and/or neurodevelopmental phenotypes. We evaluated HNF1B-related clinical features from 82 studies and reclassified 192 reported intragenic HNF1B variants. RESULTS In a prenatal case, we identified a novel in-frame deletion p.(Gly239del) within the HNF1B DNA-binding domain, a mutational hot spot as demonstrated by spatial clustering analysis and high computational prediction scores. The six postnatally diagnosed individuals harbored 17q12 microdeletions. Literature screening revealed variable reporting of HNF1B-associated clinical traits. Overall, both mutation groups showed a high phenotypic heterogeneity. The reclassification of all previously reported intragenic HNF1B variants provided an up-to-date overview of the mutational spectrum. CONCLUSIONS We highlight the value of prenatal HNF1B screening in renal developmental diseases. Standardized clinical reporting and systematic classification of HNF1B variants are necessary for a more accurate risk quantification of prenatal and postnatal clinical features, improving genetic counseling and prenatal decision making

Prenatal diagnosis of HNF1B‐associated renal cysts: Is there a need to differentiate intragenic variants from 17q12 microdeletion syndrome?

Objective 17q12 microdeletions containing HNF1B and intragenic variants within this gene are associated with variable developmental, endocrine, and renal anomalies, often already noted prenatally as hyperechogenic/cystic kidneys. Here, we describe prenatal and postnatal phenotypes of seven individuals with HNF1B aberrations and compare their clinical and genetic data to those of previous studies. Methods Prenatal sequencing and postnatal chromosomal microarray analysis were performed in seven individuals with renal and/or neurodevelopmental phenotypes. We evaluated HNF1B‐related clinical features from 82 studies and reclassified 192 reported intragenic HNF1B variants. Results In a prenatal case, we identified a novel in‐frame deletion p.(Gly239del) within the HNF1B DNA‐binding domain, a mutational hot spot as demonstrated by spatial clustering analysis and high computational prediction scores. The six postnatally diagnosed individuals harbored 17q12 microdeletions. Literature screening revealed variable reporting of HNF1B‐associated clinical traits. Overall, both mutation groups showed a high phenotypic heterogeneity. The reclassification of all previously reported intragenic HNF1B variants provided an up‐to‐date overview of the mutational spectrum. Conclusions We highlight the value of prenatal HNF1B screening in renal developmental diseases. Standardized clinical reporting and systematic classification of HNF1B variants are necessary for a more accurate risk quantification of prenatal and postnatal clinical features, improving genetic counseling and prenatal decision making