Unraveling phenotypes in Brazilian patients with cutaneous porphyrias: the impact of next generation sequencing with a targeted gene panel

Background: Cutaneous porphyrias are a heterogeneous group of both acquired and genetic disorders whose diagnosis rely on clinical features and specific biochemical testing. In Brazil, biochemical testing for acute porphyrias become more accessible in the last years, nevertheless the same was not seen for cutaneous porphyrias, so most of the key laboratory testing are performed only abroad, increasing the costs for analysis. In this context, Next Generation Sequencing (NGS) became an important tool in the investigation of patients with genetic cutaneous porphyrias.

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

Methods: Prospective data of 50 Brazilian patients with suspicion of a genetic cutaneous porphyria were collected by a national referral center for rare diseases over a 2-year period. Extracted DNA samples were analyzed using a short-read next-generation sequencing gene panel.

Results: Mutations were identified in 45 patients. All patients with clinical features of erythropoietic protoporphyria (EPP) showed a FECH mutation on one allele trans to a hypomorphic FECH IVS3-48C allele, being classified as having pseudodominant EPP. No compound heterozygotes (recessive EPP) neither ALAS2 mutations were identified in our patients. Biallelic UROS mutations were present in three unrelated patients with features of Congenital Erythropoietic Porphyria (CEP). No UROD mutations were found in 3 patients with a strong family history for Porphyria Cutanea Tarda (PPOX and CPOX mutations were not identified as well). Two pediatric patients born to unrelated families showed biallelic mutations in UROD gene, confirming the diagnosis of hepatoerythropoietic porphyria (HEP) – one of the patients had a previous diagnosis of CEP and was referred for bone marrow transplant that was put on hold after the genetic diagnosis.

Conclusions: This is the first report describing genetic variants for all cutaneous porphyrias in a sample of Brazilian patients. A genetic diagnosis allowed not only family genetic counseling but also changes in the management of patients whose clinical features could overlap, such as HEP and attenuated CEP patients. Our results also suggest that a comprehensive clinical history and physical exam can better guide the genetic testing, avoiding unnecessary and expensive laboratory tests which many times become a barrier to families in the pursuit of a rare disease diagnosis.

 

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No conflict of interest has been declared by the author(s).

Publication History

Article published online:
18 September 2023