UBTF Mutation Causes Complex Phenotype of Neurodegeneration and Severe Epilepsy in Childhood.

Introduction: Neurodegenerative diseases of childhood present with progressive decline in cognitive, social, and motor function and are frequently associated with seizures in different stages of the disease. Here we report a patient with severe progressive neurodegeneration with drug-resistant epilepsy of unknown etiology from the age of 2 years.

Methods And Results: Using whole exome sequencing, we found heterozygous missense de novo variant c.

HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels control neuronal excitability and their dysfunction has been linked to epileptogenesis but few individuals with neurological disorders related to variants altering HCN channels have been reported so far. In 2014, we described five individuals with epileptic encephalopathy due to de novo HCN1 variants. To delineate HCN1-related disorders and investigate genotype-phenotype correlations further, we assembled a cohort of 33 unpublished patients with novel pathogenic or likely pathogenic variants: 19 probands carrying 14 different de novo mutations and four families with dominantly inherited variants segregating with epilepsy in 14 individuals, but not penetrant in six additional individuals.

Detection rate of causal variants in severe childhood epilepsy is highest in patients with seizure onset within the first four weeks of life.

Background: Epilepsy is a heterogeneous disease with a broad phenotypic spectrum and diverse genotypes. A significant proportion of epilepsies has a genetic aetiology. In our study, a custom designed gene panel with 112 genes known to be associated with epilepsies was used.

Genome-wide uniparental diploidy of all paternal chromosomes in an 11-year-old girl with deafness and without malignancy.

Approximately 20 cases of genome-wide uniparental disomy or diploidy (GWUPD) as mosaicism have previously been reported. We present the case of an 11-year-old deaf girl with a paternal uniparental diploidy or isodisomy with a genome-wide loss of heterozygosity (LOH). The patient was originally tested for non-syndromic deafness, and the novel variant p.

Neonatal Onset of Epilepsy of Infancy with Migrating Focal Seizures Associated with a Novel GABRB3 Variant in Monozygotic Twins.

Background: Recently, a study providing insight into mutational spectrum was published (Møller et al 2017). The authors report considerable pleiotropy even for single mutations and were not able to identify any genotype-phenotype correlations.

Methods: The proband (twin B) was referred for massively parallel sequencing of epilepsy-related gene panel because of hypotonia and neonatal seizures.

STRC Gene Mutations, Mainly Large Deletions, are a Very Important Cause of Early-Onset Hereditary Hearing Loss in the Czech Population.

Introduction: Hearing loss (HL) is the most common sensory deficit in humans. HL is an extremely heterogeneous condition presenting most frequently as a nonsyndromic (NS) condition inherited in an autosomal recessive (AR) pattern, termed DFNB. Mutations affecting the STRC gene cause DFNB type 16.

PURA syndrome: clinical delineation and genotype-phenotype study in 32 individuals with review of published literature.

Background: De novo mutations in have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia.

Objectives: To delineate the clinical spectrum of PURA syndrome and study genotype-phenotype correlations.

Methods: Diagnostic or research-based exome or Sanger sequencing was performed in individuals with ID.

Two Novel Variants Affecting CDKL5 Transcript Associated with Epileptic Encephalopathy.

Background: Variants in the human X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been reported as being etiologically associated with early infantile epileptic encephalopathy type 2 (EIEE2). We report on two patients, a boy and a girl, with EIEE2 that present with early onset epilepsy, hypotonia, severe intellectual disability, and poor eye contact.

Methods: Massively parallel sequencing (MPS) of a custom-designed gene panel for epilepsy and epileptic encephalopathy containing 112 epilepsy-related genes was performed.

HMSN Lom in 12 Czech patients, with one unusual case due to uniparental isodisomy of chromosome 8.

Hereditary motor and sensory neuropathy-type Lom (HMSNL), also known as CMT4D, a demyelinating neuropathy with late-onset deafness is an autosomal recessive disorder threatening Roma population worldwide. The clinical phenotype was reported in several case reports before the gene discovery. HMSNL is caused by a homozygous founder mutation p.

Confirmation of the GNB4 gene as causal for Charcot-Marie-Tooth disease by a novel de novo mutation in a Czech patient.

The association of GNB4 with Charcot-Marie-Tooth (CMT) has recently been described in a publication by Soong et al. (Soong, et al., 2013).

Improving diagnosis of inherited peripheral neuropathies through gene panel analysis.

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.

Mutations in eight small DFNB genes are not a frequent cause of non-syndromic hereditary hearing loss in Czech patients.

Objectives: To evaluate the contribution of eight small NSHL-AR (non-syndromic deafness, autosomal recessive) genes to hereditary hearing loss in Czech patients.

Patients And Methods: Unrelated Czech patients, adults and children, diagnosed with pre-lingual hereditary hearing loss with at least one similarly affected deaf sibling and with previously excluded mutations in the GJB2 gene were investigated by Sanger sequencing of the selected eight small NSHL-AR associated genes (CABP2 - 51 patients, CIB2 - 45 patients, PJVK/DFNB59 - 53 patients, GJB3 - 46 patients, ILDR1 - 48 patients, LHFPL5 - 66 patients, LRTOMT - 60 patients, TMIE - 64 patients).

Results: Mutations were detected in the LHFPL5 (DFNB67) gene.

Massively Parallel Sequencing Detected a Mutation in the MFN2 Gene Missed by Sanger Sequencing Due to a Primer Mismatch on an SNP Site.

We describe a patient with early onset severe axonal Charcot-Marie-Tooth disease (CMT2) with dominant inheritance, in whom Sanger sequencing failed to detect a mutation in the mitofusin 2 (MFN2) gene because of a single nucleotide polymorphism (rs2236057) under the PCR primer sequence. The severe early onset phenotype and the family history with severely affected mother (died after delivery) was very suggestive of CMT2A and this suspicion was finally confirmed by a MFN2 mutation. The mutation p.

Spectrum and frequencies of mutations in the MFN2 gene and its phenotypical expression in Czech hereditary motor and sensory neuropathy type II patients.

The axonal type of Charcot‑Marie‑Tooth (CMT) disorders is genetically heterogeneous, therefore the causal mutation is unlikely to be observed, even in clinically well characterized patients. Mitofusin‑2 (MFN2) gene mutations are the most frequent cause of axonal CMT disorders in a number of populations. There are two phenotypes; early onset, which is severe and late onset, which is a milder phenotype.