Role of molecular genetic factors in formation of the clinical type of neurofibromatosis type 2

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Abstract

Neurofibromatosis type 2 is a hereditary disease with predisposition to the development of multiple tumors of the central and peripheral nervous system. The disease is characterized by significant variability in the clinical picture; the number of neoplasms, their location and growth rate largely determine the severity of the course. However, assessing the rate of tumor growth requires the availability of a consistent series of instrumental studies conducted within a certain time range, which is not always available at the time of initial treatment. In this study, based on quantitative (age of onset, age of examination) and qualitative (large number of intracranial tumors, large number of spinal tumors, severity of neurological symptoms, mosaic status of the genetic variant) characteristics, an alternative classification of clinical subtypes of neurofibromatosis type 2 was developed. We have revealed statistically significant differences (p-value = 0.037) in the representation of Halliday prognostic classes between the groups identified using the proposed classification which allows us to suggest the possibility of integrating this approach into clinical practice.

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About the authors

K. O. Karandasheva

Research Centre for Medical Genetics

Author for correspondence.
Email: vstrel@list.ru
Russian Federation, Moscow, 115522

E. S. Makashova

Burdenko National Medical Research Center of Neurosurgery; Loginov Moscow Clinical Scientific Center

Email: vstrel@list.ru
Russian Federation, Moscow, 125047; Moscow, 111123

F. A. Ageeva

Research Centre for Medical Genetics

Email: vstrel@list.ru
Russian Federation, Moscow, 115522

K. I. Anoshkin

Research Centre for Medical Genetics

Email: vstrel@list.ru
Russian Federation, Moscow, 115522

P. A. Sparber

Research Centre for Medical Genetics

Email: vstrel@list.ru
Russian Federation, Moscow, 115522

A. O. Borovikov

Research Centre for Medical Genetics

Email: vstrel@list.ru
Russian Federation, Moscow, 115522

P. A. Vasiluev

Research Centre for Medical Genetics

Email: vstrel@list.ru
Russian Federation, Moscow, 115522

M. S. Pashchenko

Research Centre for Medical Genetics

Email: vstrel@list.ru
Russian Federation, Moscow, 115522

A. S. Tanas

Research Centre for Medical Genetics

Email: vstrel@list.ru
Russian Federation, Moscow, 115522

V. V. Strelnikov

Research Centre for Medical Genetics

Email: vstrel@list.ru
Russian Federation, Moscow, 115522

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2. Fig. 1. Age characteristics of the study sample and results of molecular genetic testing. a – distribution of age of clinical onset (green) and age at examination (yellow) in the study sample, segment length corresponds to the duration of the disease; b – distribution density of the duration of the disease; c – frequency of occurrence of different types of mutations in the study sample, including germline (orange) and mosaic (blue) genetic variants; d – frequency of familial and sporadic cases, including germline (orange) and mosaic (blue) genetic variants.

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3. Fig. 2. FAMD of clinical features of the sample (age of onset, age at examination, severity of neurological symptoms, presence of more than 10 intracranial tumors, presence of more than 10 tumors in the spinal cord (SC), representation of the mutation in the body). a – each point corresponds to a patient, separate panels characterize sample (1) by the presence of more than 10 intracranial tumors, sample (2) – by the presence of more than 10 tumors in the spinal cord, (3) – by the representation of the pathogenic allele in the body, (4) – by the severity of the neurological status. Gray dots correspond to the absence of information on a specific feature; b, c – the contribution of the studied features to dimensions 1 and 2; d, e – the position of the features in the projection coordinates.

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4. Fig. 3. Comparison of the selected groups of tumor prevalence. a – FAMD of clinical features of the sample. Red color corresponds to group 1, yellow – to group 2, blue – to group 3. The square shape of the marker corresponds to a patient with a germline mutation, the round one – to a mosaic one; b – distribution of the age of onset in the selected groups; c – distribution of the age of examination in the selected groups; d – age of clinical onset, age of examination, duration of the disease for different categories according to Halliday in the selected groups. The orange square marker corresponds to germline variants, the blue round one – to mosaic ones.

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