The emergence of SARS-CoV-2 P.1 lineage coincided with a surge in hospitalisations in the North region of Brazil. In the South region’s Rio Grande do Sul state, severe COVID-19 case numbers rose 3.8 fold in February 2021. During that month, at a COVID-19 referral hospital in this state, whole-genome sequencing of a subset of cases’ specimens (n = 27) revealed P.1 lineage SARS-CoV-2 in most (n = 24). Findings raise concerns regarding a possible association between lineage P.1 and rapid case and hospitalisation increases.

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder characterized by the development of multiple hamartomas in many organs and tissues. It occurs due to inactivating mutations in either of the two genes, TSC1 and TSC2, following a second hit in a tumor suppressor gene in most hamartomas. Comprehensive screening for mutations in both the TSC1 and TSC2 loci has been performed in several cohorts of patients and a broad spectrum of pathogenic mutations have been described. In Brazil, there is no data regarding incidence and prevalence of tuberous sclerosis and mutations in TSC1 and TSC2. We analyzed both genes in 53 patients with high suspicion of tuberous sclerosis using multiplex-ligation dependent probe amplification and a customized next generation sequencing panel. Confirmation of all variants was done by the Sanger method. We identified 50 distinct variants in 47 (89%) of the patients. Five were large rearrangements and 45 were point mutations. The symptoms presented by our series of patients were not different between male and female individuals, except for the more common occurrence of shagreen patch in women (p = 0.028). In our series, consistent with other studies, TSC2 mutations were associated with a more severe phenotypic spectrum than TSC1 mutations. This is the first study that sought to characterize the molecular spectrum of Brazilian individuals with tuberous sclerosis.

Neurofibromatosis type 1 (NF1; MIM #162200), commonly called von Recklinghausen disease, is a frequently encountered genetic condition transmitted via autosomal dominant inheritance. It is characterized by a spectrum of neurocutaneous symptoms, such as café-au-lait patches, freckling in skin folds, various types of neurofibroma (including dermal and plexiform), as well as neurological and skeletal complications. The condition affects approximately 1 in every 3,000 to 4,000 people. Separately, cone-rod dystrophies constitute a broad category of retinal disorders that involve degeneration of both cone and rod photoreceptors and are often driven by mutations in over 100 identified genes. One such gene, CRX, is associated with autosomal dominant forms of the disease. This paper highlights an unusual clinical scenario: a patient initially diagnosed with NF1 during infancy later presented with visual impairments-specifically, myopia and astigmatism-by the age of 15 years. Genetic screening revealed two distinct variants: a pathogenic splice-site mutation in the NF1 gene (c.3871-2A) and a potentially pathogenic alteration in the CRX gene (c.119G>A). This rare combination of variants, identified through molecular diagnostics, challenges the assumption that clinical assessment alone is sufficient in NF1 cases and highlights the role of genomic analysis in refining diagnosis and management strategies.

Tuberous Sclerosis Complex: Epidemiology and manifestations

Neurofibromatosis type 1 (NF1) is a cancer predisposition syndrome that results from dominant loss-of-function mutations mainly in the NF1 gene. Large rearrangements are present in 5–10% of affected patients, generally encompass NF1 neighboring genes, and are correlated with a more severe NF1 phenotype. Evident genotype–phenotype correlations and the importance of the co-deleted genes are difficult to establish. In our study we employed an evolutionary approach to provide further insights into the understanding of the fundamental function of genes that are co-deleted in subjects with NF1 microdeletions. Our goal was to access the ortholog and paralog relationship of these genes in primates and verify if purifying or positive selection are acting on these genes. Fourteen genes were analyzed in twelve mammalian species. Of these, four and ten genes showed positive selection and purifying selection, respectively. The protein, RNF135, showed three sites under positive selection at the RING finger domain, which may have been selected to increase efficiency in ubiquitination routes in primates. The phylogenetic analysis suggests distinct evolutionary constraint between the analyzed genes. With these analyses, we hope to help clarify the correlation of the co-deletion of these genes and the more severe phenotype of NF1.