Improving diagnosis of inherited peripheral neuropathies through gene panel analysis

Abstract

Background: Inherited peripheral neuropathies (IPN) are the most common inherited neurological condition. It represents a highly heterogeneous group, both clinically and genetically. Targeted disease specific gene panel massively parallel sequencing (MPS) seems to be a useful tool in diagnosis of disorders with high genetic heterogeneity.

Methods: In our study, we have designed, validated and updated our own custom gene panel of all known genes associated with IPN. One hundred and ninety-eight patients have been tested so far. Only patients in whom mutations in more common causes or relevant genes have already been excluded were enrolled. Five consecutive panel designs were prepared according to recent literature search, the last one covering ninety-three genes. Each patient was tested only once. All data were evaluated with at least two different pipelines.

Results: In summary, causative mutation has been found in fifty-one patients (26 %). The results were inconclusive in thirty-one (16 %) patients. No variants of likely significance to IPN were found in one hundred and sixteen (58 %) patients.

Conclusion: MPS gene panel enables testing of all known IPN causes at once with high coverage and at an affordable cost making it truly a method of choice also in IPN. Gene panel testing results in several interesting results and findings.

Keywords: Charcot-Marie-Tooth; Inherited peripheral neuropathies; Mutation; Phenotype; Targeted gene panel testing.

Fig. 1

Age at onset of the disease (study cohort). For 77 % of probands included in the study the data about the age at onset of the disease were available. These are represented in the graph Age at Onset. For 23 % of probands these data were not readily available (N.A./ not available), however, age at referral for these probands is shown, as this may also be a useful surrogate (graph Age at referral). Each block in the graph represents a different age group; age groups are described as intervals in years, and percentage of probands with onset/referral is shown. From probands included in the study, 60 % of them had onset of the disease before the age of 20 years

Fig. 2

Causal variants in these genes have been found. Legend: X – axis: genes; Y – axis: number of patients with causal mutation

Fig. 3

Age of onset of the disease (patients with pathogenic mutations). Legend: The graph represents the age of onset of the disease for 51 patients with causal pathogenic mutations found in the study. Each block in the graph represents a different age of onset group; age groups are described as intervals in years, and percentage of probands with onset is shown. Almost 70 % of causal mutations were found in patients with early onset (before the age of 20), only 30 % of mutations were found in patients with onset of the disease in the third life decade or later