Mutations in the HINT1 gene were recently discovered as being the major cause of autosomal recessive axonal neuropathy with neuromyotonia. This combination was clinically recognized and described previously in a few reports but is generally unknown. We aimed to establish the importance of HINT1 mutations as the cause of hereditary neuropathy and particularly hereditary motor neuropathy/axonal Charcot-Marie-Tooth (HMN/CMT2) among Czech patients. Overall, mutations in the HINT1 gene seem to be a surprisingly frequent cause of inherited neuropathy in our group of patients. Biallelic pathogenic mutations were found in 21 patients from 19 families. The prevalent mutation in the Czech population is the p.R37P (95% of pathogenic alleles). Clinically, all patients with biallelic mutations presented with early onset of symptoms at the end of the first decade. Foot/toe extension weakness to plegia was present in almost all patients. Neuromyotonia was present in all but two patients. However, it had been properly recognized in only three patients prior to molecular genetic diagnosis. HINT1 mutations seem to be one of the most frequent causes of inherited neuropathy and are probably the most frequent cause of HMN in Czech patients. We suggest all HMN/CMT2 patients be tested for the presence of the prevalent mutation, the p.R37P.

BackgroundInherited 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.MethodsIn 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.ResultsIn 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.ConclusionMPS 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-016-0500-5) contains supplementary material, which is available to authorized users.

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Due to endogamy, the Roma have a higher risk for autosomal recessive (AR) disorders. We used homozygosity mapping on single-nucleotide polymorphism chips in one Czech Roma consanguineous family with non-syndromic hearing loss (NSHL). The second largest homozygous region in a deaf patient was mapped to the previously reported DFNB49 region. The MARVELD2 gene was recently reported as a causal gene for NSHL DFNB49. Sequencing of the MARVELD2 gene revealed a previously reported homozygous mutation c.1331+2 T>C (IVS4 + 2 T>C) in the deaf child. Subsequently, the same mutation was found in two more Roma families from an additional 19 unrelated Czech Roma patients with deafness tested for the MARVELD2 gene. To explore the importance of MARVELD2 mutations and DFNB49 for the general Czech and Central European population with early hearing loss we also tested 40 unrelated Czech patients with AR NSHL. No pathogenic mutation in the MARVELD2 gene was found in a group of 40 Czech non-Roma patients. Mutations in the MARVELD2 gene seem to be a significant cause of early NSHL in Czech Roma and this gene should be tested in this group of patients after GJB2.

Our data confirmed that variants in the CDKL5 are associated with EIEE2. There is credible evidence that the novel identified variants are pathogenic and, therefore, are likely the cause of the disease in the presented patients. In one of the patients a stop codon variant is predicted to produce a truncated protein, and in the other patient an intronic variant results in aberrant splicing.