Pediatric Von Willebrand Disease: Practice Essentials, Pathophysiology, Epidemiology
Inheritance And Genetics Of Neurofibromatosis Type 1 (NF1)
Neurofibromatosis type 1 (NF1) is a hereditary disorder caused by an alteration – called a mutation – in the NF1 gene, which is located on chromosome 17. The NF1 gene contains a code of instructions for making a protein called neurofibromin, which is produced in many cells, including nerve cells and specialized cells surrounding nerves (Schwann cells). The neurofibromin protein acts as a tumor suppressor, preventing cells from growing and dividing too rapidly. The NF1 gene mutation leads to the production of a nonfunctional or absent neurofibromin protein that is unable to regulate cell growth and division, resulting in the growth of neurofibromas (skin tumors) along nerves throughout the body.
Inherited MutationsAll people have two copies of every gene – one copy inherited from each parent. The NF1 gene mutation is dominant, which means that only one of the two copies of the gene needs to have the mutation to produce the disorder. A parent with NF1 has a 50% chance of passing the abnormal gene copy to a child. A child who inherits the altered gene will also have the disorder.
Spontaneous MutationsWhile half of the cases of NF1 are inherited from a parent, 50% of children diagnosed with NF1 appear to be the first members of their family to have the disorder. In such cases, the genetic alteration, or mutation, occurred in the sperm or egg cell that formed the child. This is called a spontaneous, or new, mutation. A person with a spontaneous mutation of the NF1 gene has a 50% chance of passing the abnormal gene copy to a child.
Determining the Source of the NF MutationIt's important to determine whether the disorder is inherited or is the result of a spontaneous mutation, since an individual with an NF1 mutation has a 50% chance of passing on the disorder every time he or she has a child. One way to accomplish this is by means of a thorough examination of each parent whose child has been diagnosed with NF1 to determine the presence of café-au-lait spots or Lisch nodules in the iris of the eyes. If neither parent is found to have signs of NF1, the child's disorder is most likely the result of a spontaneous, or new, mutation.
Genetic testing is also currently available to confirm the presence of the NF1 gene mutation with 95% sensitivity and may be appropriate in some cases. Some people have features of NF1 that are limited to only one part or one side of their body. This is called mosaic NF1 (also called segmental NF1). Mosaic NF1 is caused by a gene mutation that has arisen after conception, during early development of the person as an embryo. Genetic testing for people with type of NF, while possible, can be more complex than for individuals who do not have this form of the disorder.
What Causes the NF1 Mutation?In cases where a child's NF1 is determined to be the result of a spontaneous mutation, parents often wonder if they did something to cause the mutation, such as exposing their child to radiation, medications, alcohol, or other substances in the environment. It's important to understand that the specific cause of the NF1 gene mutation is currently unknown, and no environmental exposure has been implicated. It's also important to know that genetic mutations are not uncommon. Cells in the body are continuously dividing, and each time they do, a massive volume of genetic information must be copied correctly. Random errors inevitably occur in the copying process and may be the cause of mutations leading to NF1.
Genetic Changes Alone Cannot Explain Tumor Growth In NF-1 Patients
Despite what was previously thought, new research has shown that genetic changes alone cannot explain why and where tumours grow in those with genetic condition neurofibromatosis type 1 (NF-1). Understanding more about the factors involved could, in the future, facilitate early cancer detection in NF-1 patients and even point towards new treatments.
Researchers from the Wellcome Sanger Institute, UCL Great Ormond Street Institute of Child Health, Great Ormond Street Hospital, Cambridge University Hospitals NHS Foundation Trust, and their collaborators, focused on NF-1, a genetic condition that causes specific types of tumours, and investigated how and why these developed.
The study, published today (25 February) in Nature Genetics, reports that the genetic changes thought to cause tumours can be found in normal tissues throughout the body, suggesting that other factors are also necessary for tumour development.
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Subscribe for FREEThey also uncovered a pattern of changes in the affected gene, NF1, that may explain why the nervous system in particular is a common site for these tumours to develop.
Understanding what other factors are involved in developing these tumours could help inform monitoring programmes for patients with NF-1, who require regular screening to detect tumours early on and could potentially require multiple surgeries and chemotherapy.
In the future, refining our knowledge of why tumours grow in some places and not others may help us identify the patients most likely to need early medical intervention.
This model of tumour development is not unique to NF-1, raising the possibility that similar events occur in related genetic conditions, meaning many more could benefit from tailored management.
NF-1 is a genetic condition that causes brown skin patches, similar to birthmarks, and tumours1. While the tumours are often benign, they can become cancerous over time and may cause a range of symptoms depending on where they are1. For example, NF-1 can cause soft tissue and brain tumours that may restrict movement and vision.
The symptoms and impact of NF-1 can vary greatly from person to person. It is one of the most common inherited genetic conditions, impacting around one in 2500 people, with approximately 25,000 people in the UK living with this condition2. Those with NF-1 have a genetic change that means one copy of the gene encoding the neurofibromin protein, NF1, does not work. It was previously thought that tumours and brown skin patches occurred when the second copy of the gene was lost.
In a new study, researchers from the Sanger Institute, UCL Great Ormond Street Institute of Child Health, Great Ormond Street Hospital, Cambridge University Hospitals NHS Foundation Trust, and their collaborators, studied nearly 500 tissue samples from a child with NF-1 and compared them to tissues from children without the condition.
They found that changes causing a loss of NF1 gene function were not limited to tumours and skin changes but instead can be found throughout other tissues of the child with NF-1 as well. This suggests, whilst advantageous to the affected cells, the mutation is insufficient to cause tumour formation.
For this research, the team applied a new sequencing technology that allowed them to look at genetic changes at a higher resolution than was previously possible and studied additional tissue samples from nine adults with NF-1, showing similar findings.
The team found a pattern of mutations across all patients that showed these were particularly common in tissues of the nervous system. This is a common place for tumours to form in those with NF-1, which can help explain why these tissues are specifically impacted.
Dr Thomas Oliver, co-first author from the Wellcome Sanger Institute and Cambridge University Hospitals NHS Foundation Trust, said: "We were astonished to see such extensive genetic changes in the normal tissues of patients with NF-1, seemingly without consequence. This is contrary to our understanding of tumour development in the condition and other related conditions. Additional factors must clearly play a role, perhaps including the cell type and anatomical location affected. Whilst further investigation is needed, I hope this work represents the first step towards developing more personalised care for these patients, such as better identifying who is at greater risk of developing tumours, and adjusting screening to intervene early on and minimise complications."
Professor Thomas Jacques, co-senior author from UCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital, said: "NF-1 can have many different impacts on a person's life. In order to better treat and support those with NF-1, we have to understand more about what is going on at a biological and genetic level, especially in the parts of the body that are most affected, such as the brain and nervous system. Our study showed that these areas of the body have a different pattern of DNA changes, suggesting that if we look further, there could be a potential target for new therapies to help treat or stop tumour development."
Professor Sam Behjati, co-senior author from the Wellcome Sanger Institute and Cambridge University Hospitals NHS Foundation Trust, said: "Loss of the second NF1 gene had always been thought to cause tumours in individuals with NF-1. Our findings fundamentally question this decade-old paradigm and force us to rethink how tumours arise, to pave the way for better screening, prevention, and treatment of cancers."
Reference: Oliver TRW, Lawson ARJ, Lee-Six H, et al. Cancer-independent somatic mutation of the wild-type NF1 allele in normal tissues in neurofibromatosis type 1. Nat Genet. 2025. Doi: 10.1038/s41588-025-02097-2
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NEXT GEN SEQUENCING AND DELETION/DUPLICATION ANALYSIS OF NF1 And SPRED1 ONLY (NFSP-NG)
NEXT GEN SEQUENCING AND DELETION/DUPLICATION ANALYSIS OF NF1 and SPRED1 ONLY (NFSP-NG)Acceptable specimen types:
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TEST DESCRIPTION
The DNA-based NF1/SPRED1-only by NGS involves sequencing as well as deletion/duplication analysis of the entire coding NF1/SPRED1 regions plus the alternatively spliced NF1 exons 9br, 23a and 48a (67 exons total). The test uses an extensively customized and optimized set of Agilent HaloPlex capture probes, followed by sequencing of overlapping amplicons within the regions of interest using Illumina sequencing chemistry. Each coding exon plus ~50bp of flanking intronic sequence are simultaneously sequenced. 5' and 3' untranslated sequences are not included. The average coverage is >2000x with >99.8% of the NF1 coding region ≥350x and 100% ≥200x, allowing detection of very low level mosaicism, down to 3-5% MAF respectively (regions covered by ≥350x respectively ≥200x). Variant and copy number calls are made using a unique bioinformatics pipeline detecting all types of mutations including single nucleotide substitutions, indels, and frameshifts caused by deletion/ duplication up to 112bp.
Based on >15 years of experience with comprehensive RNA-based NF1 testing, we designed the customized and optimized NGS NF1-component of the assay to comprise all regions encountered through analysis of >15,000 unrelated individuals including >8,100 NF1-mutation-positive individuals carrying 1 out of >3,100 different unique NF1 mutations identified in the UAB MGL cohort. Included in the NGS assay are the regions covering >65 different deep intronic splice mutations (which reside beyond the +/-50 intronic base pairs that flank all exons). Validation of the full panel included, besides substitutions (missense, nonsense, splice variants), the most challenging mutations such as insertions/deletions/duplications of 1-112bp (~25% of the UAB NF1 cohort) and one-to-multiple exon deletions/duplications (~2.8% of the UAB NF1 cohort). The analytical sensitivity of our NGS testing approach was 100% for substitutions as well as insertion/deletions up to 112bp. This panel has not yet been validated to identify deletions/duplications >112bp and <1 exon, but such mutations have not yet been found in the UAB cohort, and therefore are likely very rare. The panel has been validated for the detection of germline (heterozygous) single-exon deletions/duplications as well as multi-exon deletions/duplications, however mosaic single-exon deletion/duplications validation is still pending. Single exon deletions/duplications are present in ~0.45% of NF1-positive patients from the UAB cohort with 9% of these individuals being mosaic (~0.045% of all in the UAB NF1-positive cohort). Detection of Alu/LINE insertions, identified in 0.25% of patients from the UAB NF1-positive cohort, has not yet been validated using the current NGS approach.
With the largest dataset of NF1 genotypes matched with phenotypes, any genotype-phenotype correlations identified will be reported in real time.
Confirmatory testing of reportable variants is performed by Sanger sequencing or other orthogonal methods.For novel NF1 variants of unknown significance, we offer free of charge targeted RNA-based testing to assess the effect of the variant on splicing and enhance the correct classification/ interpretation.
Relevant family members of a proband with any (novel or previously identified) variant of unknown significance are offered free of charge targeted analysis as long as accurate phenotypic data are provided by a health care professional to enhance the interpretation. There is no limitation to the number of relatives that can be tested free of charge.Mosaicism is often present in sporadic patients with an NF1 microdeletion and has important repercussions for counseling. Free of charge evaluation by FISH analysis on 200 interphase chromosomes is offered in such cases.
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Note: Detailed and accurate completion of this document is necessary for reporting purposes. The Medical Genomics Laboratory issues its clinical reports based on the demographic data provided by the referring institution on the lab requisition form. It is the responsibility of the referring institution to provide accurate information. If an amended report is necessary due to inaccurate or illegible documentation, additional reports will be drafted with charge.
Requests for Molecular Genetic testing will not be accepted for the following reasons:
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