Clinical and molecular characterization of neurofibromatosis in southern Brazil

<p><b>Objectives</b>: Neurofibromatoses (type 1: NF1; type 2: NF2) are autosomal dominant tumor predisposition syndromes mostly caused by loss-of-function mutations in the tumor suppressor genes NF1 and NF2, respectively. Genotyping is important for correct diagnosis of these diseases. The authors aimed to characterize <i>NF1</i> and <i>NF2</i> variants in patients from Southern Brazil.</p> <p><b>Methods</b>: Ninety-three unrelated probands with NF1 and 7 unrelated probands with NF2 features were recruited from an Oncogenetics center in Southern Brazil. Two next generation sequencing panels were customized to identify point mutations: NF1 (<i>NF1, RNF135</i>, and <i>SUZ12</i> genes) and NF2 (<i>NF2</i> and <i>SMARCB1</i> genes). Large rearrangements were assessed by Multiplex Ligation-dependent Probe Amplification.</p> <p><b>Results</b>: Sixty-eight heterozygous <i>NF1</i> variants were identified in 75/93 probands (80%) and 3 heterozygous <i>NF2</i> variants were identified in 3/7 probands (43%). In <i>NF1</i>, 59 (87%) variants were pathogenic (4 large rearrangements – 6%), 6 (9%) were likely pathogenic, 3 (4%) were variants of uncertain significance and 28 (41%) were novel. In <i>NF2</i>, all variants were pathogenic. No novel genotype-phenotype correlations were observed; however, previously described correlations were confirmed in our cohort.</p> <p><b>Conclusion</b>: The clinical and molecular characterization of neurofibromatoses in different populations is very important to provide further insights into the pathogenesis of these diseases.</p

Bacterial phylotypes that differed between controls and patients with phenylketonuria, based on White’s non-parametric <i>t</i>-test.

<p>Bacterial phylotypes that differed between controls and patients with phenylketonuria, based on White’s non-parametric <i>t</i>-test.</p

Comparison of phenylketonuria and control groups.

<p>Comparison of phenylketonuria and control groups.</p

Frequencies of most abundant phyla (>1% of group sequences) in the phenylketonuria (n = 8) and control (n = 10) groups.

<p>*<i>p</i>-value < 0.05. Top panel represents the average abundance per treatment. Bottom panel represents the average of phyla per patient.</p

Alpha diversity measurements of microbial communities in the phenylketonuria and control groups.

<p>Each panel represent one alpha diversity measure as follow: Observed = total number of OTU’s observed; Chao1 and ACE = richness estimators (estimate the total number of OTU’s present in a community); Shannon, Simpson and InvSimpson = microbial indexes of diversity. Boxes span the first to third quartiles; the horizontal line inside the boxes represents the median. Whiskers extending vertically from the boxes indicate variability outside the upper and lower quartiles, and the single black circles indicate outliers.</p

Families with a likely benign or variant of uncertain significance in <i>TSC1</i> and <i>TSC</i>.

<p>Families with a likely benign or variant of uncertain significance in <i>TSC1</i> and <i>TSC</i>.</p

Molecular analysis of <i>TSC1</i> and <i>TSC2</i> genes and phenotypic correlations in Brazilian families with tuberous sclerosis

<div><p>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, <i>TSC1</i> and <i>TSC2</i>, following a second hit in a tumor suppressor gene in most hamartomas. Comprehensive screening for mutations in both the <i>TSC1</i> and <i>TSC2</i> 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 <i>TSC1</i> and <i>TSC2</i>. 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, <i>TSC2</i> mutations were associated with a more severe phenotypic spectrum than <i>TSC1</i> mutations. This is the first study that sought to characterize the molecular spectrum of Brazilian individuals with tuberous sclerosis.</p></div

Phenotypic comparison between male and female individuals with TSC.

<p>Phenotypic comparison between male and female individuals with TSC.</p