The AGT Epistasis Pattern Proposed a Novel Role for ZBED9 In Regulating Blood Pressure: Tehran Cardiometabolic Genetic Study (TCGS)

Backgroung: Hypertension is typically considered as the leading risk factor for cardiovascular disease. Epistasis studies may add another layer of complexity to our understanding of the genetic basis of hypertension. Methods: A nested case-control design was used on 4214 unrelated Tehran Cardiometabolic Genetic Study (TCGS) adults to evaluate 65 SNPs of previously associated genes, including ZBED9, AGT, and TNXB. The integrated effect of each gene was determined using the Sequence-based Kernel Association Test (SKAT). We used model-based multifactor dimension reduction (Mb-MDR) and entropy-based gene-gene interaction (IGENT) methods to determine interaction and epistasis patterns. Results: The integrated effect of each gene has a statistically significant association with blood pressure traits (P-value < 0.05). Single-locus analysis identified two missense variants in ZBED9 (rs450630) and AGT (rs4762) that are associated with hypertension. In the ZBED9 gene, significant local interactions were discovered. The G allele in rs450630 showed an antagonistic effect on hypertension, but interestingly, IGENT analysis revealed significant epistasis effects for different combinations of ZBED9, AGT, and TNXB loci. Conclusion: We discovered a novel interaction effect between a significant variant in an essential gene for hypertension (AGT) and a missense variant in ZBED9, which has shifted our focus to ZBED9's role in blood pressure regulation.

Clinicopathological investigation of secretory carcinoma cases including a successful treatment outcome using entrectinib for high-grade transformation: a case report

Background Secretory carcinoma (SC) of the salivary gland is a recently described malignant tumor harboring characteristic ETV6-NTRK3 gene fusion. SC generally has a favorable clinical course, and is currently regarded as a low-grade carcinoma. However, a small subset of SCs demonstrates aggressive clinical features with histologically high-grade transformed morphology, the molecular pathogenesis of which has not yet been elucidated. In this study, we performed a clinicopathological and molecular genetic study of patients with SC of the head and neck displaying various clinical characteristics to investigate the differences of pathological and molecular genetics between low-grade and high-grade components of SC. Case presentation Three cases with SC of the head and neck, including a conventional low-grade SC and two high-grade transformed SCs are described. High-grade transformed SCs with histological features such as nuclear polymorphism, distinctive nucleoli and increased mitotic activity developed locoregional recurrence and distant metastasis. Immunohistochemical analysis revealed that low- and high-grade components showed different expression patterns for S-100 protein and mammaglobin, whereas all examined components were positive for p-STAT5. p53-positive cell population was markedly higher in one case with high-grade transformed SC. The proliferative activity of high-grade components was markedly increased, with the Ki-67 labeling index ranging up to 30–32%. A fluorescence in situ hybridization study with an ETV6 (12p13) break apart probe revealed split signals in the nuclei in all 3 cases. A targeted next-generation sequencing-based fusion assay demonstrated that all 6 clinical samples from the 3 patients showed the presence of the ETV6-NTRK3 fusion transcripts. One patient with high-grade transformed SC showed a dramatic clinical response to the pan-TRK inhibitor, entrectinib, for the treatment of locoregional recurrence and pulmonary metastasis. Conclusions High-grade transformed SC showed aggressive clinical and pathological features with increased Ki-67 labeling index. Molecular genetic study of gene rearrangement appears to be beneficial treatment as the presence of ETV6-NTRK3 translocation may represent a therapeutic target in SC, particularly the high-grade transformed type.

Les Soixante-quinze Feuillets de Marcel Proust ou la fabrique du masque

Les Soixante-quinze Feuillets by Marcel Proust or the production of the mask In Search of Lost Time, the narrator is not the writer, and we can find out several models behind one character. In other words, Proust created a mask he put on reality to avoid criticism and problems with his family, but also to look for the essence of beings and things by focusing the truth. Pseudonyms are not a game but a real poetic of the Name. The recent publication of his Soixante-quinze Feuillets (Gallimard, 2021) shows how Proust transformed his autobiography into a fictional world. That preliminary version exposes the methods he used to hide himself and the way he was experimenting the powers of the imagination and composition. It is the writer’s laboratory, an important source for genetic study of Proust’s masterpiece.

Spatial population genetic structure and colony dynamics in Damaraland mole-rats (Fukomys damarensis) from the southern Kalahari

Background Non-random associations within and among groups of social animals can provide valuable insight into the function of group living and the evolution of social behaviour. Damaraland mole-rats (Fukomys damarensis) demonstrate extremely high levels of reproductive skew, and dispersal is considered to be male-biased in onset and frequency, although asymmetry in dispersal distance is yet to be investigated. Dispersal may be positively correlated with increasing favourable environmental conditions, such as rainfall, however, the effects of ecological constraints on dispersal and colony fission–fusion dynamics have not previously been demonstrated on a spatial scale. Here we provide the first spatial population genetic study for this species. We investigated genetic structure in a population of Damaraland mole-rats from the southern Kalahari in South Africa over 3 years, combining observational dispersal data from mark-recapture with population genetic data to evaluate (1) sex-bias in frequency and distance of dispersal in this species, and (2) the effect of rainfall on fission–fusion dynamics of colonies. Results Our results demonstrate (1) that both males and females favour local dispersal but on rare occasions may disperse over distances greater than 400 m, (2) that males may disperse over greater distances than females, and (3) that males more frequently immigrate into established neighbouring colonies than females, who predominantly disperse by colony fission, i.e. multiple individuals “budding” from their native colony into a neighbouring territory, thereby establishing new colonies. Furthermore, our results demonstrate (4) elevated dispersal and colony fission in association with increased rainfall, supporting the hypothesis that rainfall may play a significant role in the maintenance and/or disruption of reproductive skew in Damaraland mole-rat populations. Conclusion This study represents the first fine-scale spatial population genetic study in Damaraland mole-rats, and provides relevant insights into colony fission–fusion dynamics in a social and cooperatively breeding species.

Abstract 16747: Rapidly Lethal Dilated Cardiomyopathy Secondary To Generalized Arterial Calcification Of Infancy

Case Presentation: A previously healthy 3-month-old infant presented with cardiorespiratory arrest, from which she was successfully resuscitated. A dilated cardiomyopathy with severely depressed systolic function was diagnosed. ECG showed high voltage QRS complexes and generalized alteration of repolarization. In the following 12 hours, she suffered 2 other cardiac arrests, recuperated with defibrillation. Hemodinamic stability was achieved but brain death was diagnosed 36 hours after the onset of symptoms. Autopsy showed striking calcification of the right and left coronary arteries, with narrowing of the arterial lumen, causing extensive subendocardial infarction. Calcification also affected the aorta, pulmonary arteries, thyroid, kidney and other splanchnic arteries. Generalized arterial calcification of infancy (GACI) was diagnosed and a genetic study found two biallelic variants in ABCC6 gene: p.Arg1114Cys and p.Trp38Ser, both previously described in elastic pseudoxanthoma (PXE), but not in GACI. Genotyping of the healthy parents confirmed genetic segregation with biallelic variants. Discussion: GACI is an extremely rare genetic disease characterized by widespread arterial calcification and narrowing of large and medium-sized vessels. The usual clinical presentation is heart failure in fetal life or in the first months of infancy. In most cases it is lethal, with death occurring within a few hours or days after the onset of symptoms, although clinical involvement is highly variable and cases with long survival have been described. GACI is an autosomal recessive disease secondary to biallelic variants in the ENPP1 gene (67% of cases) and in the ABCC6 gene (9%). The variants found in our patient had not been previously described in GACI, just in PXE, a much milder disease with usually normal lifespan. This case confirms that both entities reflect two extremes of a clinical spectrum of ectopic calcification instead of two different disorders. The aim of presenting this case is to remind clinicians of this rare etiology in neonates or infants with dilated cardiomyopathy. In case of death, autopsy should always be requested. When this condition is diagnosed, genetic study will be positive in 75% of cases, allowing prenatal counseling.