Gene sequencing in patients with primary iron overload

A hemocromatose é uma doença autossômica recessiva, causada por uma diminuição na concentração de hepcidina ou uma redução na ligação entre hepcidina e ferroportina. A principal variante genética associada à hemocromatose é a p.Cys282Tyr em homozigose no gene HFE. Outras variantes nos genes HJV, HAMP, TFR2, SLC40A1, BMP6 e FTL também têm sido associadas à sobrecarga de ferro. Este projeto possui dois objetivos, sendo o primeiro deles efetuar o sequenciamento, através de metodologia de Sanger, nos éxons dos genes citados, em amostras de pacientes com sobrecarga de ferro cujas causas secundárias foram excluídas e não possuem a variante p.Cys282Tyr em homozigose no gene HFE. O segundo objetivo foi realizar divulgação científica sobre hemocromatose através do Grupo Brasileiro de Hemocromatose (GBH). O sequenciamento dos genes BMP6 e FTL foi realizado e após a análise foram encontradas duas variantes patogênicas e uma variante de significado incerto (VUS) no gene BMP6, sendo que duas delas não foram descritas em literatura. Estes resultados renderam a publicação de um artigo científico. Para o gene FTL foi encontrada uma variante patogênica já descrita e a partir deste resultado foi publicado um case report. O gene HFE foi sequenciado em todos os pacientes, mas não foram obtidos resultados concretos, e devido à falta de financiamento não foi possível sequenciar os demais genes (HJV, HAMP, TFR2 e SLC40A). Além dos artigos citados, também foi publicada uma revisão a respeito da hemocromatose e um trabalho sobre qualidade de vida em pacientes com hemocromatose. A identificação de variantes patogênicas no gene BMP6 e FTL podem contribuir para a compreensão genética da sobrecarga de ferro e projetos no modelo do GBH são de extrema importância para a educação em saúde, contribuindo para a democratização da informação, prevenção da doença e qualidade de vida.Hemochromatosis is an autosomal recessive disease, caused by a decrease in hepcidin concentration or reduction of a binding between hepcidin and ferroportin. The main genetic variant associated with hemochromatosis is the homozygous p.Cys282Tyr in the HFE gene. Other variants in the HJV, HAMP, TFR2, SLC40A1, BMP6 and FTL genes have also been associated with iron overload. This project has two objectives, the first of which is controlled sequencing, through Sanger's methodology, in the exons of the mentioned genes, in the selection of patients with iron overload whose secondary causes have been excluded and who do not have a homozygous p.Cys282Tyr variant in the HFE gene. The second objective was to carry out scientific dissemination on hemochromatosis through the Brazilian Group of Hemochromatosis (GBH). The sequencing of the BMP6 and FTL genes was carried out and after the analysis, two pathogenic variants and a variant of uncertain significance (VUS) were found in the BMP6 gene, two of which have not been described in the literature. These results resulted in the publication of a scientific article. For the FTL gene, a previously described pathogenic variant was found and based on this result, a case report was published. The HFE gene was sequenced in all patients, but no concrete results were obtained, and due to lack of funding it was not possible to sequence the other genes (HJV, HAMP, TFR2 and SLC40A). In addition to the cited articles, a review on hemochromatosis and a study on quality of life in patients with hemochromatosis was also published. The identification of pathogenic variants in the BMP6 and gene can contribute to the genetic understanding of iron overload and projects in the GBH model are of extreme importance for health education, confident for the democratization of information, disease prevention and quality of life.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)00

Haemochromatosis revisited

International audienceHaemochromatosis is a genetic disease caused by hepcidin deficiency, responsible for an increase in intestinal iron absorption. Haemochromatosis is associated with homozygosity for the HFE p.Cys282Tyr mutation. However, rare cases of haemochromatosis (non-HFE haemochromatosis) can also be caused by pathogenic variants in other genes (such as HJV, HAMP, TFR2 and SLC40A1). A working group of the International Society for the Study of Iron in Biology and Medicine (BIOIRON Society) has concluded that the classification based in different molecular subtypes is difficult to be adopted in clinical practice and has proposed a new classification approaching clinical questions and molecular complexity. The aim of the present review is to provide an update on classification, pathophysiology and therapeutic recommendations

Quality of Life Scores Remained Different among the Genotypic Groups of Patients with Suspected Hemochromatosis, Even after Treatment Period

International audienceBACKGROUND: Hemochromatosis is a genetic condition of iron overload caused by deficiency of hepcidin. In a previous stage of this study, patients with suspected hemochromatosis had their quality of life (QL) measured. We observed that QL scores differed among genotypic groups of patients. In this reported final phase of the study, the aims were to compare QL scores after a treatment period of approximately 3 years and to analyze a possible association of the serum ferritin values with QL scores. METHODS: Sixty-five patients were enrolled in this final phase and divided into group 1 (patients that showed primary iron overload and homozygous genotype for the HFE p.Cys282Tyr mutation) and group 2 (other kinds of genotypes). Short Form 36 (SF-36) was performed and consisted of eight domains with a physical and also a mental component. RESULTS: Both groups had a significant decrease in serum ferritin concentrations: group 1 had a variation from 1844 ± 1313 ng/mL to 281 ± 294 ng/mL, and group 2 had a variation from 1216 ± 631 ng/mL to 236 ± 174 ng/mL. Group 1 had a smaller mean value for these six SF-36 domains compared with group 2, indicating a worse QL. CONCLUSIONS: In this final stage, six domains demonstrated a difference among genotypic groups (role emotional and mental health, adding to the four of the initial phase), reassuring the impact of the identified genotype on the QL of hemochromatosis patients. Furthermore, despite that both patient groups demonstrated similar and significant decreases in serum ferritin values, no association was found between the decrease in this biological parameter and the SF-36 domains

Novel mutations in the bone morphogenetic protein 6 gene in patients with iron overload and non-homozygous genotype for the HFE p.Cys282Tyr mutation

International audienceBackground - Five main genes are associated with hemochromatosis; however, current studies show that, in addition to these genes, others may be associated with primary iron overload (IO). One of these is the bone morphogenetic protein 6 (BMP6), which encodes a protein that modulates hepcidin synthesis and, consequently, iron homeostasis. Aim - To identify BMP6 gene pathogenic variants in patients with IO and non-homozygous genotype for the HFE p.Cys282Tyr mutation. Materials and methods - Fifty-three patients with primary IO and non-homozygous genotype for the HFE p.Cys282Tyr were selected. Subsequent bidirectional DNA sequencing of BMP6 exons was performed. Results - Two novel variants were found. One at homozygous state p.Gln158Ter (c.472C>T) was pathogenic, the other one at heterozygous state p.Val394Met (c.1180G>A) was of uncertain significance (VUS); the third variant at heterozygous state p.Arg257His (c.770G>A) has already been described and associated with IO. No BMP6 pathogenic variants that would explain iron overload phenotypes were detected in 94% of the studied patients. Conclusion - Identification of the BMP6 pathogenic variants in Brazilian patients with primary IO might contribute to the genetic understanding of this phenotype