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Proceedings of the 24th Annual Meeting of the Portuguese Society of Human Genetics (SPGH – Sociedade Portuguesa de Genética Humana)
63 auth. J. Peláez, Rita Monteiro, Silvana Lobo, Liliana Sousa, H. Pinheiro, S. Castedo, L. Garrido, Manuel, Teixeira, G. Michils, Vicent Bours, Robin de Putter, L. Golmard, Maud Blanluet, C. Colas, ...
Compared to wild type iPSC-CMs at day 30 of the mutant iPSC-CMs showed increased cellular size, multinucleation, and disorganized sarcomeres, thus recapit-ulating HCM-speci fi c features. Reduced levels of MYBPC3 and myosin binding protein-C were det…
Compared to wild type iPSC-CMs at day 30 of the mutant iPSC-CMs showed increased cellular size, multinucleation, and disorganized sarcomeres, thus recapit-ulating HCM-speci fi c features. Reduced levels of MYBPC3 and myosin binding protein-C were detected in mutant cells. Sequencing analysis revealed skipping of exon 12 in mutant Exon 12 skipping causes frameshift and introduces a premature termination codon. Treatment with cycloheximide fi rmed that of revising the classi fi cation of HCM- associated missense mutations in the MYBPC3 gene. Germline CDH1 Pathogenic (P) and Likely Pathogenic (LP) variants are actionable variants in Hereditary Diffuse Gastric Cancer (HDGC), predisposing for diffuse gastric cancer (DGC) and lobular breast cancer (LBC). While asymptomatic P/LP variant carriers undergo intensive stomach/breast surveillance and prophylactic surgery to avoid disease, the clinical management of carriers of CDH1 variants of unknown signi fi cance (VUS) remains unsolved. Almost all missense variants are classi fi ed as VUS, while predicted truncating variants and large rearrangements are more often classi fi ed as P/LP. We aimed to study, at using genotype-phenotype analysis, CDH1 -associated disease spectrum and age-of- disease onset to improve VUS classi fi cation. Among European Reference Network ERN-GENTURIS collaborators from 10 European countries, we collected and registered phenotypes from 854 families carrying CDH1 germline variants. We classi fi ed all variants according to the CDH1 -ACMG clinical classi fi cation. From 854 families, 194 carried truncating variants, from which 88% were P/LP and 12% were VUS, 71% ful fi lling clinical criteria. Among 607 phenotypes from P/LP variants, DGC was the most prevalent phenotype (37%) followed by LBC (10%), both at an average of onset (AOO) below 51. Families carrying truncating-P/LP and truncating-VUS showed an equivalent phenotype distribution and frequency of ful fi llment of clinical criteria, suggesting a potentially clinical actionability for these VUS, that we called ‘ hot VUS ’ . In contrast, in families carrying missense-VUS (433 probands+relatives), 92% lacking clinical criteria, DGC and LBC together accounted for < 10% of the phenotypes. This phenotype distribution overlapped that of benign/likely benign carrier families, and for this, they were called ‘ cold VUS ’ . Our study encloses the largest dataset of CDH1 variant carriers ever studied for genotype-phenotype analysis and the fi rst formally demonstrating potential differences in clinical actionability of CDH1 VUS, supported by phenotypical presentations. CDH1 missense VUS are most likely cold- VUS, that rather than causal of HDGC, may represent important phenotype modi fi ers. detected CUBN variants potentially implicated in the phenotype. Pt 1 presented the c.6928_6934del p. (Glu2310Cysfs ∗ 3) in compound heterozygosity with c.5597C > T p.(Pro1866Leu). Pt 2 was a compound heterozygote for c.6007A > T p.(Arg2003 ∗ ) and c.5840C > A p.(Ser1947Tyr). Joint analysis of the siblings (Pts 3 and 4) revealed variants c.1512C > G p.(Ile504Met) and c.7379T > C p.(Ile2460Thr). In this case, the patients ’ parents were not available for genetic study.Four variants herein reported have not been described before. The characteristics of Pts 1 and 2 are in accordance with previous descriptions of CUBN-affected individuals: were diagnosed in infancy, present a stable clinical state, and have CUBN variants in the C-terminal domains. In contrast, Pts 3 and 4 have a more severe kidney disease, an uncommon fi nding for CUBN patients. One of their variants is in one of the N-terminal domains. This, however, does not exclude its clinical relevance, as similar variants have been described as a cause of proteinuria when combined with a C-terminal pathogenic alteration. In this family, additional studies are being performed to investigate the potential pathogenicity of these variants. OCT4 and SOX2 gene expression in GD3 neural progenitor cells was comparable to the gene expression in GD3 patient fi broblasts. The ZEB2 gene expression was higher in GD3 fi broblasts than in GD3 neural progenitor cells. The gene expression behavior of all neurogenesis genes ( NES , MAP2 and OTX2 ) was similar but higher expression was observed in GD3 hiPSCs than in GD3 neural progenitor cells. version. The impact of uORFs on Bmpr1a expression suggests that expression of 5 ’ -UTR with different lengths may affect the fi delity of ribosome translation under different cellular con-ditions.Analysis of the Bmpr1a 3 ’ -UTR identi fi ed a putative conserved CDE. Two versions of this region were inserted into the 3 ’ -end of a reporter luciferase plasmid: a shorter version without CDE, identi fi ed from a pre-osteoblast MC3T3 cells; and a longer version including a CDE, identi fi ed from a cDNA library of mouse liver tissue. The results obtained indicate that Bmpr1a transcripts are subject to a complex regulation depending on the cellular context. In proliferating MC3T3 cells, the 3 ’ - UTR identi fi ed was shorter and should favour Bmpr1a translation. Longer versions of 3 ’ -UTR identi fi ed in liver tissue suggest a distinct Bmpr1a regulation in differentiated hepatocytes. Additional studies are required to understand its impact on translation. environmental nature. In Portugal, the mean prevalence of hypertension in the population is 45.5%. Objective: The aim of this study is to evaluate the contribution of anthropometric, physiological, and genetic factors (e NOS and ACE ) to the development of hypertension in a Portuguese population. Methods: A case-control study was conducted in a sample of 377 individuals, 243 hypertensives, and 134 normotensives. The polymorphic analyses of intron 4 VNTR in the eNOS gene and the insertion/deletion (I/D) in ACE gene were performed by polymerase chain reaction (PCR). Results: High body mass index (BMI) values, high glycemia levels, and the 4a allele of the eNOS were associated with hypertension. Among the hypertensive group, the allele 4a ( eNOS ) was associated with high levels of HbA1c, and the D allele ( ACE ) with glycemia. Conclusion: Our results highlight the contribution of eNOS and ACE genes as important players for the onset and development of hypertension in the Portuguese population. We believe that a combinatory clinical approach including the traditional anthropomorphic and physiological parameters together with genetic studies can be more elucidative in establishing a susceptibility pro fi le on multifactorial conditions as hypertension. an X-linked neurodevelopmental condition caused by mutations in cyclin-depen-dent kinase-like 5 ( CDKL5 ) gene resulting in the loss-of-function of its encoded protein - a serine/threonine kinase- essential for normal brain development and function. Patients suffering from this rare disorder present early-onset seizures, which begin in the fi rst months of life and a regression in neurological and motor development. Although a genetic cause for this condition was identi fi ed, the association between the type/location of mutations and patient ’ s phenotype and the mechanisms responsible for its onset remain unclear. Mouse models developed to mimic CDD are unable to develop seizures, a central feature of this condition in humans. Therefore, the use of other models such as zebra fi sh represent an alternative tool to study this syndrome. In this work we investigated the effect of mutant CDKL5 using a dominant negative approach in zebra fi sh thus expecting to contribute to unveil the molecular pathways involved in the onset of CDD. For that, we produced CDKL5 RNA harboring the mutation c.1708G > T found in a CDD patient presenting recurrent seizures, gross motor hypotonia and poor eye contact, and injected it into zebra fi sh embryos to look for possible phenotypes analogous to those observed in the human clinical condition. The resulting mutant protein (p.E570X) is truncated and lacks the C-terminus motifs responsible for its nuclear localization and exportation. Bioinformatic analysis con fi rmed the high degree of conservation between human and zebra fi sh CDKL5 gene structure and protein sequence. Motor behavior was evaluated using the Zantiks equipment and a seizure behavior was observed in wildtype 5dpf larvae exposed to PTZ, a seizure-inducing drug. We are currently performing this behavioral analysis in larvae expressing the CDKL5 dominant negative form. Altogether, our results support the use of zebra fi sh as a valid alternative model to study guidance. This work reinforces the idea that basic cellular processes may compromise neuronal development and synaptic signaling such as cell signaling at the immune system level (interleukin function), MAP kinase or G alpha signaling. logistic regression models identi fi ed both SCRIB (OR = 0.11, p = 0.015) and PIK3CB (OR = 0.041, p = 0.04) with a signi fi cant predictive value associated with the development of metastasis/ relapse. Conclusion: This study gave a step forward in the identi fi cation of prognosis biomarkers with great potential for patients ’ management. heterogeneity and analysis of the HBB gene cluster has revealed fi ve distinct haplotypes: Senegal (SEN), Benin (BEN), Central African Republic (CAR), Cameroon (CAM) and Arab-Indian (ARAB). The aim of this study was to assess the frequency of HBB haplotypes, as well as to correlate other genetic predictors that could have an impact on SCD phenotype in an Angolan pediatric population.Thisstudy analyzed clinical and biological data collected from 192 Angolan children. DNA was extracted from peripheral blood samples and paired-end sequencing was performed using the NextSeq 550. Haplotype classi fi cation was based on four previously described SNPs (rs3834466, rs28440105, rs10128556, and rs968857) and the genotype for the SNPs in HBG2 (rs7482144 ) , BCL11A (rs4671393) and HBS1L-MYB (rs28384513, rs4895441) genes were also obtained. study of multiple variants. These results empha
Published in
Medicine
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