148:
In silico Analysis Of Alterations In ANGPT1 Gene Supports A New Pathway Responsible To Mediate Hereditary Angioedema In Brazilian Patients With No Mutations In SERPING1 And F12 Genes.
Saturday, March 3, 2018
South Hall A2 (Convention Center)
Nathália Cagini, MsC, Camila Lopez Veronez, PhD, Bruna Franca Azevedo, Rosemeire Navickas Constantino-Silva, PhD, Renan Paulo Martin, PhD, Jane da Silva, PhD, Anete S. Grumach, PhD, João Bosco Pesquero, PhD
RATIONALE: Hereditary angioedema (HAE) is classified as: C1-INH-HAE with mutations in SERPING1 gene and C1-INH deficiency; FXII-HAE characterized by mutation in F12 gene and normal C1-INH and U-HAE with normal C1-INH but unknown pathogenesis. Angiopoietin 1 antagonizes the action of VEGF on vascular permeability, suggesting that an alteration of this gene could lead to the increase permeability and to trigger edema.

METHODS: The SERPING1 and F12 genes of 73 patients with HAE were sequenced by Sanger but no alterations were detected. ANPGT1 gene was analyzed and the alterations found were submitted to in silico analysis in the predictors PolyPhen-2, SIFT (Scale-Invariant Feature Transform), PROVEAN (Protein Variation Effect Analyzer), MutationTaster, LRT (Likelihood Radio Test) and CADD (Combined Annotation Dependent Depletion). DNA samples from men and women 12 to 75 years old were analyzed. 82 control individuals comprising C1-INH-HAE and FXII-HAE patients and healthy donors were also analyzed.

RESULTS: Two variants were found in U-HAE patients. The variant p.Ala8Val (c.23C>T) was found in two different families. In silico analysis considered as disease causing in three of them (MutationTaster-score 0,998; LRT-score 0,0; CADD-score 18,65). The p.Gln370His (c.1110G>C) was found in members of a family, three of six in silico predictors considered it as disease causing (MutationTaster-score 1,0; LRT-score 1,0; CADD-score 22,6). The variants were not found in controls.

CONCLUSIONS: Those in silico analysis provide pathogenic supporting evidence according to The American College of Medical Genetics and Genomics – ACMG. Those finds open new range of studies to differents pathophysiologies involved in U-HAE.