Genotype-phenotype correlation in neurofibromatosis type-1: NF1 whole gene deletions lead to high tumor-burden and increased tumor-growth

Well, Lennart; Döbel, K.-U.; Bannas, Peter; Farschtschi, Said; Adam, Gerhard; Mautner, Victor‐Felix; Salamon, Johannes

doi:10.1371/journal.pgen.1009517

Cited by 18 publications

(15 citation statements)

References 38 publications

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“…In our cohort, symptomatic spinal neurofibromas were significantly more frequent in the NF1-deleted patients (6/35 vs. 36/2,058; p value = 1.7 × 10 −4 after correction for multiple testing). Altogether, NF1-deleted patients had a higher tumor burden than non-deleted NF1 patients [64].…”

Section: Discussionmentioning

confidence: 92%

Severe Phenotype in Patients with Large Deletions of NF1

Pacot¹,

Vidaud²,

Sabbagh³

et al. 2021

Cancers

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Complete deletion of the NF1 gene is identified in 5–10% of patients with neurofibromatosis type 1 (NF1). Several studies have previously described particularly severe forms of the disease in NF1 patients with deletion of the NF1 locus, but comprehensive descriptions of large cohorts are still missing to fully characterize this contiguous gene syndrome. NF1-deleted patients were enrolled and phenotypically characterized with a standardized questionnaire between 2005 and 2020 from a large French NF1 cohort. Statistical analyses for main NF1-associated symptoms were performed versus an NF1 reference population. A deletion of the NF1 gene was detected in 4% (139/3479) of molecularly confirmed NF1 index cases. The median age of the group at clinical investigations was 21 years old. A comprehensive clinical assessment showed that 93% (116/126) of NF1-deleted patients fulfilled the NIH criteria for NF1. More than half had café-au-lait spots, skinfold freckling, Lisch nodules, neurofibromas, neurological abnormalities, and cognitive impairment or learning disabilities. Comparison with previously described “classic” NF1 cohorts showed a significantly higher proportion of symptomatic spinal neurofibromas, dysmorphism, learning disabilities, malignancies, and skeletal and cardiovascular abnormalities in the NF1-deleted group. We described the largest NF1-deleted cohort to date and clarified the more severe phenotype observed in these patients.

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Section: Discussionmentioning

confidence: 92%

Severe Phenotype in Patients with Large Deletions of NF1

Pacot¹,

Vidaud²,

Sabbagh³

et al. 2021

Cancers

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“…Patients with type-1 NF1 deletions often exhibit a severe clinical phenotype characterized by features that are not frequently seen in patients with intragenic pathogenic NF1 variants such as dysmorphic facial features, severe global developmental delay, cognitive disability, increased MPNST risk and a high number (as well as an accelerated growth rate) of neurofibromas (reviewed by Kehrer-Sawatzki et al 2017 , 2020 ; Ottenhoff et al 2020 ; Büki et al 2021 ; Pasmant et al 2021 ; Pacot et al 2021 ; Well et al 2021 ). Genes located within the type-1 NF1 deletion interval and co-deleted with NF1 are likely to be responsible for the severe NF1 microdeletion-associated phenotype giving rise to the NF1 microdeletion syndrome.…”

Section: Discussionmentioning

confidence: 99%

“…Further, MPNSTs may occur significantly earlier in patients with NF1 microdeletions as compared with NF1 patients with intragenic pathogenic variants (De Raedt et al 2003 ). Higher numbers of subcutaneous and plexiform neurofibromas and higher growth rates of these tumours have been observed in patients with NF1 microdeletions as compared to patients with intragenic pathogenic NF1 variants (Well et al 2021 ). In addition, many patients with NF1 microdeletions exhibit features which are not usually observed in patients with pathogenic variants within the NF1 gene including facial dysmorphic features, overgrowth, severe global developmental delay and intellectual disability (reviewed by Kehrer-Sawatzki et al 2017 , 2020 ; Ottenhoff et al 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Classification of NF1 microdeletions and its importance for establishing genotype/phenotype correlations in patients with NF1 microdeletions

Kehrer‐Sawatzki

Cooper

2021

Hum Genet

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An estimated 5–11% of patients with neurofibromatosis type-1 (NF1) harbour large deletions encompassing the NF1 gene and flanking regions. These NF1 microdeletions are subclassified into type 1, 2, 3 and atypical deletions which are distinguishable from each other by their extent and by the number of genes included within the deletion regions as well as the frequency of mosaicism with normal cells. Most common are type-1 NF1 deletions which encompass 1.4-Mb and 14 protein-coding genes. Type-1 deletions are frequently associated with overgrowth, global developmental delay, cognitive disability and dysmorphic facial features which are uncommon in patients with intragenic pathogenic NF1 gene variants. Further, patients with type-1 NF1 deletions frequently exhibit high numbers of neurofibromas and have an increased risk of malignant peripheral nerve sheath tumours. Genes located within the type-1 NF1 microdeletion interval and co-deleted with NF1 are likely to act as modifiers responsible for the severe disease phenotype in patients with NF1 microdeletions, thereby causing the NF1 microdeletion syndrome. Genotype/phenotype correlations in patients with NF1 microdeletions of different lengths are important to identify such modifier genes. However, these correlations are critically dependent upon the accurate characterization of the deletions in terms of their extent. In this review, we outline the utility as well as the shortcomings of multiplex ligation-dependent probe amplification (MLPA) to classify the different types of NF1 microdeletion and indicate the importance of high-resolution microarray analysis for correct classification, a necessary precondition to identify those genes responsible for the NF1 microdeletion syndrome.

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“…In children and adolescents with NF1 microdeletions, cutaneous and subcutaneous neurofibromas are more frequent than in patients of the same age with intragenic NF1 mutations [17]. Furthermore, patients with type-1 NF1 microdeletions exhibit more often plexiform neurofibromas as well as an increased growth rate of these tumors as compared to patients with pathogenic intragenic NF1 gene variants [18].…”

Section: Why and When To Order Genetic Testing For Nf1mentioning

confidence: 99%

The NF1 microdeletion syndrome: early genetic diagnosis facilitates the management of a clinically defined disease

Kehrer‐Sawatzki

Bäzner

Krämer

et al. 2022

J Deutsche Derma Gesell

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SummaryNeurofibromatosis type‐1 (NF1) is a genodermatosis frequently encountered in general dermatology. In many patients, the diagnosis of NF1 is made clinically based on the presence of café‐au‐lait macules and skinfold freckling, as well as plexiform neurofibromas detectable during early childhood. Later in life, cutaneous neurofibromas often represent important diagnostic features. NF1 is characterized by extreme clinical variability and a broad heterogeneity of NF1 gene mutations which impede genotype/phenotype correlations. Notable exceptions are NF1 microdeletions observed in 5–11 % of all NF1 patients. Patients with NF1 microdeletions frequently exhibit facial dysmorphic features and a tall stature as rather specific clinical signs. Furthermore, cutaneous and subcutaneous neurofibromas present at an early age, severe global developmental delay and cognitive disability are pathognomonic for the “NF1 microdeletion syndrome”. Importantly, NF1 microdeletions are associated with an approximately twofold higher risk for malignant peripheral nerve sheath tumors than intragenic NF1 gene mutations. The severe clinical manifestations of patients with NF1 microdeletions require early multidisciplinary clinical care and frequent tumor surveillance. Therefore, when red flag features for the “NF1 microdeletion syndrome” are present in a patient, genetic testing is necessary to confirm or exclude an NF1 microdeletion.

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Genotype-phenotype correlation in neurofibromatosis type-1: NF1 whole gene deletions lead to high tumor-burden and increased tumor-growth

Cited by 18 publications

References 38 publications

Severe Phenotype in Patients with Large Deletions of NF1

Severe Phenotype in Patients with Large Deletions of NF1

Classification of NF1 microdeletions and its importance for establishing genotype/phenotype correlations in patients with NF1 microdeletions

The NF1 microdeletion syndrome: early genetic diagnosis facilitates the management of a clinically defined disease

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