Do non-pathogenic variants of DNA mismatch repair genes modify neurofibroma load in neurofibromatosis type 1?

Child s Nervous System ◽

10.1007/s00381-021-05436-w ◽

2022 ◽

Author(s):

Anja Harder

Keyword(s):

Mismatch Repair ◽

Neurofibromatosis Type 1 ◽

Neurofibromatosis Type ◽

Tumour Suppressor Genes ◽

Gene Variants ◽

Single Nucleotide Variants ◽

Dna Mismatch ◽

Pathogenic Variants ◽

Patients At Risk

AbstractNon-pathogenic mismatch repair (MMR) gene variants can be associated with decreased MMR capacity in several settings. Due to an increased mutation rate, reduced MMR capacity leads to accumulation of somatic sequence changes in tumour suppressor genes such as in the neurofibromatosis type 1 (NF1) gene. Patients with autosomal dominant NF1 typically develop neurofibromas ranging from single to thousands. Concerning the number of neurofibromas NF1 patients face a situation that is still not predictable. A few studies suggested that germline non-pathogenic MMR gene variants modify the number of neurofibromas in NF1 and by this mechanism may promote the extent of neurofibroma manifestation. This review represents first evidence that specific non-pathogenic single nucleotide variants of MMR genes act as a modifier of neurofibroma manifestation in NF1, highlighting MSH2 re4987188 as the best analysed non-pathogenic variant so far. In summary, besides MSH2 promotor methylation, specific non-pathogenic germline MSH2 variants are associated with the extent of neurofibroma manifestation. Those variants can serve as a biomarker to facilitate better mentoring of NF1 patients at risk.

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Genotype-Phenotype Correlations in Neurofibromatosis Type 1: A Single-Center Cohort Study

Cancers ◽

10.3390/cancers13081879 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1879

Author(s):

Marcello Scala ◽

Irene Schiavetti ◽

Francesca Madia ◽

Cristina Chelleri ◽

Gianluca Piccolo ◽

...

Keyword(s):

Neurofibromatosis Type 1 ◽

Neurofibromatosis Type ◽

Copy Number Variations ◽

Single Nucleotide Variants ◽

Multivariate Statistical ◽

Gene Deletions ◽

Pathogenic Variants ◽

Lisch Nodules ◽

Next Generation Sequencing Ngs

Neurofibromatosis type 1 (NF1) is a proteiform genetic condition caused by pathogenic variants in NF1 and characterized by a heterogeneous phenotypic presentation. Relevant genotype–phenotype correlations have recently emerged, but only few pertinent studies are available. We retrospectively reviewed clinical, instrumental, and genetic data from a cohort of 583 individuals meeting at least 1 diagnostic National Institutes of Health (NIH) criterion for NF1. Of these, 365 subjects fulfilled ≥2 NIH criteria, including 235 pediatric patients. Genetic testing was performed through cDNA-based sequencing, Next Generation Sequencing (NGS), and Multiplex Ligation-dependent Probe Amplification (MLPA). Uni- and multivariate statistical analysis was used to investigate genotype–phenotype correlations. Among patients fulfilling ≥ 2 NIH criteria, causative single nucleotide variants (SNVs) and copy number variations (CNVs) were detected in 267/365 (73.2%) and 20/365 (5.5%) cases. Missense variants negatively correlated with neurofibromas (p = 0.005). Skeletal abnormalities were associated with whole gene deletions (p = 0.05) and frameshift variants (p = 0.006). The c.3721C>T; p.(R1241*) variant positively correlated with structural brain alterations (p = 0.031), whereas Lisch nodules (p = 0.05) and endocrinological disorders (p = 0.043) were associated with the c.6855C>A; p.(Y2285*) variant. We identified novel NF1 genotype–phenotype correlations and provided an overview of known associations, supporting their potential relevance in the implementation of patient management.

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Challenges in the diagnosis of neurofibromatosis type 1 (NF1) in young children facilitated by means of revised diagnostic criteria including genetic testing for pathogenic NF1 gene variants

Human Genetics ◽

10.1007/s00439-021-02410-z ◽

2021 ◽

Author(s):

Hildegard Kehrer-Sawatzki ◽

David N. Cooper

Keyword(s):

Young Children ◽

Diagnostic Criteria ◽

Neurofibromatosis Type 1 ◽

Early Adulthood ◽

Neurofibromatosis Type ◽

Clinical Feature ◽

Pathogenic Variants ◽

Legius Syndrome ◽

Nf1 Gene

AbstractNeurofibromatosis type 1 (NF1) is the most frequent disorder associated with multiple café-au-lait macules (CALM) which may either be present at birth or appear during the first year of life. Other NF1-associated features such as skin-fold freckling and Lisch nodules occur later during childhood whereas dermal neurofibromas are rare in young children and usually only arise during early adulthood. The NIH clinical diagnostic criteria for NF1, established in 1988, include the most common NF1-associated features. Since many of these features are age-dependent, arriving at a definitive diagnosis of NF1 by employing these criteria may not be possible in infancy if CALM are the only clinical feature evident. Indeed, approximately 46% of patients who are diagnosed with NF1 later in life do not meet the NIH diagnostic criteria by the age of 1 year. Further, the 1988 diagnostic criteria for NF1 are not specific enough to distinguish NF1 from other related disorders such as Legius syndrome. In this review, we outline the challenges faced in diagnosing NF1 in young children, and evaluate the utility of the recently revised (2021) diagnostic criteria for NF1, which include the presence of pathogenic variants in the NF1 gene and choroidal anomalies, for achieving an early and accurate diagnosis.

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Constitutional mismatch repair deficiency as a differential diagnosis of neurofibromatosis type 1: consensus guidelines for testing a child without malignancy

Journal of Medical Genetics ◽

10.1136/jmedgenet-2018-105664 ◽

2018 ◽

Vol 56 (2) ◽

pp. 53-62 ◽

Cited By ~ 12

Author(s):

Manon Suerink ◽

Tim Ripperger ◽

Ludwine Messiaen ◽

Fred H Menko ◽

Franck Bourdeaut ◽

...

Keyword(s):

Differential Diagnosis ◽

Mismatch Repair ◽

Neurofibromatosis Type 1 ◽

Healthy Child ◽

Neurofibromatosis Type ◽

Mismatch Repair Deficiency ◽

Repair Deficiency ◽

Legius Syndrome ◽

Constitutional Mismatch Repair Deficiency

Constitutional mismatch repair deficiency (CMMRD) is a rare childhood cancer predisposition syndrome caused by biallelic germline mutations in one of four mismatch-repair genes. Besides very high tumour risks, CMMRD phenotypes are often characterised by the presence of signs reminiscent of neurofibromatosis type 1 (NF1). Because NF1 signs may be present prior to tumour onset, CMMRD is a legitimate differential diagnosis in an otherwise healthy child suspected to have NF1/Legius syndrome without a detectable underlying NF1/SPRED1 germline mutation. However, no guidelines indicate when to counsel and test for CMMRD in this setting. Assuming that CMMRD is rare in these patients and that expected benefits of identifying CMMRD prior to tumour onset should outweigh potential harms associated with CMMRD counselling and testing in this setting, we aimed at elaborating a strategy to preselect, among children suspected to have NF1/Legius syndrome without a causative NF1/SPRED1 mutation and no overt malignancy, those children who have a higher probability of having CMMRD. At an interdisciplinary workshop, we discussed estimations of the frequency of CMMRD as a differential diagnosis of NF1 and potential benefits and harms of CMMRD counselling and testing in a healthy child with no malignancy. Preselection criteria and strategies for counselling and testing were developed and reviewed in two rounds of critical revisions. Existing diagnostic CMMRD criteria were adapted to serve as a guideline as to when to consider CMMRD as differential diagnosis of NF1/Legius syndrome. In addition, counselling and testing strategies are suggested to minimise potential harms.

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