Polygen Defi-Alpha: Genetic Polymorphisms Study in Children With Alpha-1 Antitrypsin Deficiency, Included in the DEFI-ALPHA Cohort

The deficiency of alpha-1 antitrypsin (DA1AT) is a genetic disorder of variable clinical expression, initially described in adults with pulmonary emphysema patients. In children, it is the second cause of neonatal cholestasis after biliary atresia and is a common indication for liver transplantation. Several genotypes for SERPINA1 gene coding for alpha-1 anti-trypsin were identified. The main ones are M / M, M / Z, M / S and Z / Z and each genotype is closely correlated with the concentration of blood A1AT. The estimate for France suggests a prevalence of genotype deficit Z / Z of the order of 1/6054, (9982 patients), which in 11% of cases, have liver disease (prolonged neonatal jaundice). Half of them will move towards the development of cirrhosis with portal hypertension, at worst liver transplantation. Currently, we do not know what are the clinical and genetic factors that predispose a patient A1AT deficiency develop liver damage. Recent studies have led us to think that polymorphisms in the gene SERPINA1, as well as that of the alpha-mannosidase 1 endoplasmic reticulum (Erman gene) could be a predictive marker of liver complications. Another possible candidate gene is one of the importin beta (KPNB1), a protein involved in the elimination of misfolded proteins. These data lead us to propose the study of genetic polymorphisms. The main objective of the study is to compare the allele frequencies of these polymorphisms between (i) a cohort of A1AT deficient patients and with hepatic symptoms (portal hypertension and its complications, severe liver failure leading to transplant or not, or an indication for liver transplantation) and (ii) a cohort of A1AT deficient patients without signs of hepatic call. To build this last cohort, we will include in the genetic study the family members of deficient patients, some of whom probably carrying a deficit genotype Z / Z but without any associated clinical manifestations. This will allow us to facilitate the establishmen