Next generation sequencing in the diagnosis of Acute Hepatic Porphyrias (AHP): unraveling the molecular basis of AHP in Brazilian patients

Background: In Brazil, analyses of clinical and laboratory features of patients with acute porphyrias are until recently limited to biochemical testing since genetic testing was expensive and not covered by national health system neither private insurance. In partnership with Brazilian Porphyria Association (ABRAPO), during February 2020 until March 2022, genetic testing was offered to patients registered in the patient's database to better allow a specific diagnosis for the families.

Objective: To report the findings of a genetic comprehensive analysis performed in Brazilian patients with clinical and/or biochemical features of acute porphyrias.

Methods: Individuals aged ≥16 years from a Brazilian national referral center for porphyrias with a suspected diagnosis or a confirmed history of AHP that underwent genetic testing via ABRAPO between February 2020 and March 2022 were included. Extracted DNA samples from saliva and buccal swabs were analyzed using a short-read next-generation sequencing gene panel.

Results: Overall, of the 122 unrelated individuals referred for AHP molecular diagnostic testing, 80 had an AHP mutation. Although most mutations identified were in hydroxymethylbilane synthase gene (HMBS n= 43), there was an unexpected great number of pathogenic variants in protoporphyrinogen oxidase (PPOX n= 31) in patients with a previous biochemical diagnosis of Acute Intermittent Porphyria (AIP). Just one heterozygous variant in ALAD gene was seen in our cohort in a patient with a pathogenic mutation in PPOX gene. Of the 250 family members of mutation-positive individuals tested for an autosomal dominant AHP, 104 (46.8%) had their respective family mutation. All patients with documented increase in aminolevulinic acid and porphobilinogen had a confirmed molecular diagnosis of AHP.

Conclusions: This is the first report describing genetic variants for all four acute porphyrias in Brazilian individuals under AHP investigation. It was worthy of note that a high number of cases of VP was identified with PPOX mutations, being a frequent cause of AHP in our population. These data expand the molecular genetic heterogeneity of the AHP and document the usefulness of molecular testing to confirm the positive biochemical findings in symptomatic patients and identify at-risk asymptomatic family members. A correct genetic diagnosis allows not only better understanding of such disorders but also genetic counseling for affected and at-risk individuals.

 

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Publikationsverlauf

Artikel online veröffentlicht:
18. September 2023