Patterns of Novel Alleles and Genotype/Phenotype Correlations Resulting from the Analysis of 108 Previously Undetected Mutations in Patients Affected by Neurofibromatosis Type I

Bonatti, Francesco; Adorni, Alessia; Matichecchia, Annalisa; Mozzoni, Paola; Uliana, Vera; Pisani, Francesco; Garavelli, Livia; Graziano, Claudio; Gnoli, Maria; Carli, Diana; Bigoni, Stefania; Boschi, Elena; Martorana, Davide

doi:10.3390/ijms18102071

Cited by 11 publications

(16 citation statements)

References 32 publications

(39 reference statements)

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“…Seventy‐three distinct intragenic NF1 variants found in the current study have a similar distribution pattern found in previous studies thus confirming the absence of hot‐spot regions (Barrea et al., 2018; Bonatti et al., 2017; Kang et al., 2020; Terzi et al., 2007). According to previous studies, most of the germline pathogenic NF1 variants appear to cause truncation of the gene product, often by altering mRNA splicing (Friedman, 1993; Palma Milla et al., 2018).…”

Section: Discussionsupporting

confidence: 91%

Neurofibromatosis type 1: Expanded variant spectrum with multiplex ligation‐dependent probe amplification and genotype–phenotype correlation in 138 Turkish patients

Güneş

Yeşil

Geyik

et al. 2021

Annals of Human Genetics

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Objective To investigate the variant spectrum and genotype–phenotype correlations in a Turkish cohort with Neurofibromatosis Type‐1 (NF1). Materials and methods We retrospectively investigated the clinical and molecular data of 138 NF1 patients from 129 families who had been followed‐up for a median of 3.9 (1.25–18.5) years. Results NF1 sequencing revealed 73 different intragenic variants, 19 of which were novel. Seven large deletions were detected by multiplex ligation‐dependent probe amplification (MLPA) analyses. The total detection rate of pathogenic NF1 variants was found to be 87.1%. Comparing age groups, cutaneous neurofibromas, freckling, and Lisch nodules were more prevalent in patients older than 12 years (p > .05). Optic glioma detected in 17.3% of the patients and was significantly more common before the age of 6 (p > .001). Other solid tumors developed in 5% of the patients. There was no genotype–phenotype correlation between patients with truncating and nontruncating variants. However, six out of seven patients with large deletions had significant developmental delay, one patient with the c.2970_2972delAAT (p.Met992del) variant had only typical pigmentary features, and another patient with the c.4267A > G (p.Lys1423Glu) variant had CALMs, freckling, neurofibromas, and Noonan‐like phenotype. Conclusions We described 19 novel variants and seven large deletions in NF1. Applying MLPA assay in NF1 is useful in expanding the molecular diagnosis. Although very limited genotype–phenotype correlation has been reported in NF1, the fact that specific phenotypic findings were observed in our patients with large deletions and two intragenic variants supports the studies published recently.

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Section: Discussionsupporting

confidence: 91%

Neurofibromatosis type 1: Expanded variant spectrum with multiplex ligation‐dependent probe amplification and genotype–phenotype correlation in 138 Turkish patients

Güneş

Yeşil

Geyik

et al. 2021

Annals of Human Genetics

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“…A total of 309 NF1 patients were selected on the basis of the inclusion and exclusion criteria and included in the study; 255 were recruited from the authors' institutions (92 with OPG and 163 without OPG) and 54 were retrieved from the recent literature (40 with OPG and 14 without OPG) [33][34][35][36][37][38][39][40][41]. One hundred and thirty-two patients were included in the NF1 OPG group (61 females, 57 males; the sex of 14 patients retrieved from the literature was not reported) and 177 in the NF1 non-OPG group (91 females, 76 males; 10 unknown).…”

Section: Resultsmentioning

confidence: 99%

“…The literature review allowed us to select 54 patients; there were more patients in the OPG group (40) than in the non-OPG group (14) [33][34][35][36][37][38][39][40][41].…”

Section: Literature Reviewmentioning

confidence: 99%

Risk of Optic Pathway Glioma in Neurofibromatosis Type 1: No Evidence of Genotype–Phenotype Correlations in a Large Independent Cohort

Melloni

Eoli

Cesaretti

et al. 2019

Cancers

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The occurrence of optic pathway gliomas (OPGs) in children with neurofibromatosis type 1 (NF1) still raises many questions regarding screening and surveillance because of the lack of robust prognostic factors. Recent studies of an overall cohort of 381 patients have suggested that the genotype may be the main determinant of the development of OPG, with the risk being higher in patients harbouring NF1 mutations in the 5’ tertile and the cysteine/serine-rich domain. In an attempt to confirm this hypothesis, we used strict criteria to select a large independent cohort of 309 NF1 patients with defined constitutional NF1 mutations and appropriate brain images (255 directly enrolled and 54 as a result of a literature search). One hundred and thirty-two patients had OPG and 177 did not. The association of the position (tertiles and functional domains) and type of NF1 mutation with the development of OPG was analysed using the χ2 test and Fisher’s exact probability test; odds ratios (ORs) with 95% confidence intervals were calculated, and Bonferroni’s correction for multiple comparisons was applied; multiple logistic regression was also used to study genotype–phenotype associations further. Our findings show no significant correlation between the site/type of NF1 mutation and the risk of OPG, and thus do not support the hypothesis that certain constitutional mutations provide prognostic information in this regard. In addition, we combined our cohort with a previously described cohort of 381 patients for a total of 690 patients and statistically re-analysed the results. The re-analysis confirmed that there were no correlations between the site (tertile and domain) and the risk of OPG, thus further strengthening our conclusions.

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“…Hence, identification and providing information of pathologic mutations are important, even more to sporadic patients who are usually diagnosed later than familial cases. Besides the direct-sequencing method of genomic DNA, supplementary tests (reverse transcription PCR of total RNA, MLPA, FISH), which have been used in the present study, can be helpful to identify specific genotypes of patients [ 20 , 24 , 25 ]. The ongoing recognition of different mutations may give insights into the still unknown mechanisms involved in the development of NF1, allowing further genotype-phenotype correlations.…”

Section: Discussionmentioning

confidence: 99%

Clinical and molecular characterization of 112 single-center patients with Neurofibromatosis type 1

et al. 2018

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BackgroundThe aim of this retrospective study was to define clinical and molecular characteristics of a large sample of neurofibromatosis type 1 (NF1) patients, as well as to evaluate mutational spectrum and genotype-phenotype correlation. NF1 is a relatively common neurogenetic disorder (1:2500–1:3000 individuals). It is caused by mutations of the NF1 gene on chromosome 17ql1.2, with autosomal dominant pattern of inheritance and wide phenotypical variability. Café-au-lait spots (CALs), cutaneous and/or subcutaneous neurofibromas (CNFs/SCNFs), skinfold freckling, skeletal abnormalities, Lisch nodules of the iris and increased risk of learning and intellectual disabilities, as well as tumors of the nervous system and other organs are its main clinical features.MethodsThe preliminary group collected 168 subjects with clinical suspicion of NF1. They were evaluated following the National Institutes of Health (NIH) criteria for NF1, revised by Gutmann et al. 1997, integrated for 67 of them by molecular testing. According to these references, 112 of 168 patients were diagnosed as NF1. The sample was characterized by an equal sex ratio (57 males, 55 females) and age distribution ranging from 10 days to 60 years of age (mean age, 13 years).ResultsA wide spectrum of clinical features has been observed in our patients. Mutational analysis resulted positive in 51 cases (76%). Twenty-four mutations detected in our cohort have not been reported to date.ConclusionsThis study may contribute to a better definition of genotypic and phenotypic features of NF1 patients, with respect to further insights into the clinical characterization of the disease. In addition, an amplification of the spectrum of mutations in the NF1 gene has been documented.

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Patterns of Novel Alleles and Genotype/Phenotype Correlations Resulting from the Analysis of 108 Previously Undetected Mutations in Patients Affected by Neurofibromatosis Type I

Cited by 11 publications

References 32 publications

Neurofibromatosis type 1: Expanded variant spectrum with multiplex ligation‐dependent probe amplification and genotype–phenotype correlation in 138 Turkish patients

Neurofibromatosis type 1: Expanded variant spectrum with multiplex ligation‐dependent probe amplification and genotype–phenotype correlation in 138 Turkish patients

Risk of Optic Pathway Glioma in Neurofibromatosis Type 1: No Evidence of Genotype–Phenotype Correlations in a Large Independent Cohort

Clinical and molecular characterization of 112 single-center patients with Neurofibromatosis type 1

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