Yield of exome sequencing in patients with developmental and epileptic encephalopathies and inconclusive targeted gene panel.

Objective: Developmental and epileptic encephalopathies (DEEs) are a group of severe, early-onset epilepsies characterised by refractory seizures, developmental delay, or regression and generally poor prognosis. DEE are now known to have an identifiable molecular genetic basis and are usually examined using a gene panel. However, for many patients, the genetic cause has still not been identified.

The NBN founder mutation-Evidence for a country specific difference in age at cancer manifestation.

Background: Nijmegen breakage syndrome (NBS) is an autosomal-recessive chromosome instability disorder characterized by, among others, hypersensitivity to X-irradiation and an exceptionally high risk for lymphoid malignancy. The vast majority of NBS patients is homozygous for a common Slavic founder mutation, c.657del5, of the NBN gene, which is involved in the repair of DNA double-strand breaks (DSBs).

Czech family confirms the new 1p36.13-1p36.12 microdeletion syndrome.

Confirmation of the newly described 1p36.13-1p36.12 microdeletion syndrome by finding of a 2,2 Mb deletion in the critical region in a Czech two generation family with a very similar phenotype, but in addition also polyneuropathy of lower limbs.

SPG11: clinical and genetic features of seven Czech patients and literature review.

SPG11 is one of the most frequent autosomal recessively inherited types of hereditary spastic paraplegias (HSP or SPG). We describe the first seven patients from the Czech Republic with biallelic pathogenic variants in the SPG11. The typical HSP neurological findings are present in all the described patients in that the signs of a complicated phenotype develop slowly.

Dominant KPNA3 Mutations Cause Infantile-Onset Hereditary Spastic Paraplegia.

Objective: Hereditary spastic paraplegia (HSP) is a highly heterogeneous neurologic disorder characterized by lower-extremity spasticity. Here, we set out to determine the genetic basis of an autosomal dominant, pure, and infantile-onset form of HSP in a cohort of 8 patients with a uniform clinical presentation.

Methods: Trio whole-exome sequencing was used in 5 index patients with infantile-onset pure HSP to determine the genetic cause of disease.

Severe neurodevelopmental disorder with intractable seizures due to a novel SLC1A4 homozygous variant.

Introduction: Biallelic variants in the SLC1A4 gene have been so far identified as a very rare cause of neurodevelopmental disorders with or without epilepsy and almost exclusively described in the Ashkenazi-Jewish population.

Patients And Methods: Here we present Czech patient with microcephaly, severe global developmental delay and intractable seizures whose condition remained undiagnosed despite access to clinical experience and standard diagnostic methods including examination with an epilepsy targeted NGS gene panel.

Results: Whole exome sequencing revealed a novel variant NM_003038.

The Cause of Hereditary Hearing Loss in Heterozygotes-A Comprehensive Study of the /DFNB1 Region.

Hearing loss is a genetically heterogeneous sensory defect, and the frequent causes are biallelic pathogenic variants in the gene. However, patients carrying only one heterozygous pathogenic (monoallelic) variant represent a long-lasting diagnostic problem. Interestingly, previous results showed that individuals with a heterozygous pathogenic variant are two times more prevalent among those with hearing loss compared to normal-hearing individuals.

Biallelic variants in the SORD gene are one of the most common causes of hereditary neuropathy among Czech patients.

Recently, biallelic variants in the SORD gene were identified as causal for axonal hereditary neuropathy (HN). We ascertained the spectrum and frequency of SORD variants among a large cohort of Czech patients with unknown cause of HN. Exome sequencing data were analysed for SORD (58 patients).

The High Affinity Dopamine D Receptor Agonist MCL-536: A New Tool for Studying Dopaminergic Contribution to Neurological Disorders.

The dopamine D receptor exists in two different states, D and D; the former is the functional form of the D receptor and associates with intracellular G-proteins. The D agonist [H]MCL-536 has high affinity for the D receptor ( 0.8 nM) and potently displaces the binding of (-(-)---propylnorapomorphine (NPA; 0.

The genetic landscape of axonal neuropathies in the middle-aged and elderly: Focus on .

Objective: To test the hypothesis that monogenic neuropathies such as Charcot-Marie-Tooth disease (CMT) contribute to frequent but often unexplained neuropathies in the elderly, we performed genetic analysis of 230 patients with unexplained axonal neuropathies and disease onset ≥35 years.

Methods: We recruited patients, collected clinical data, and conducted whole-exome sequencing (WES; n = 126) and single-gene sequencing (n = 104). We further queried WES repositories for variants and measured blood levels of the -encoded protein neprilysin.

Spectrum and frequencies of non GJB2 gene mutations in Czech patients with early non-syndromic hearing loss detected by gene panel NGS and whole-exome sequencing.

Non-syndromic autosomal recessive hearing loss is an extremely heterogeneous disease caused by mutations in more than 80 genes. We examined Czech patients with early/prelingual non-syndromic, presumably genetic hearing loss (NSHL) without known cause after GJB2 gene testing. Four hundred and twenty-one unrelated patients were examined for STRC gene deletions with quantitative comparative fluorescent PCR (QCF PCR), 197 unrelated patients with next-generation sequencing by custom-designed NSHL gene panels and 19 patients with whole-exome sequencing (WES).

Variant c.2158-2A>G in MANBA is an important and frequent cause of hereditary hearing loss and beta-mannosidosis among the Czech and Slovak Roma population- evidence for a new ethnic-specific variant.

Background: The Roma are a European ethnic minority threatened by several recessive diseases. Variants in MANBA cause a rare lysosomal storage disorder named beta-mannosidosis whose clinical manifestation includes deafness and mental retardation. Since 1986, only 23 patients with beta-mannosidosis and biallelic MANBA variants have been described worldwide.

Clinical features and blood iron metabolism markers in children with beta-propeller protein associated neurodegeneration.

Background: Neurodegeneration with brain iron accumulation constitutes a group of rare progressive movement disorders sharing intellectual disability and neuroimaging findings as common denominators. Beta-propeller protein-associated neurodegeneration (BPAN) represents approximately 7% of the cases, and its first signs are typically epilepsy and developmental delay. We aimed to describe in detail the phenotype of BPAN with a special focus on iron metabolism.

Demyelinating Charcot-Marie-Tooth neuropathy associated with FBLN5 mutations.

Background And Purpose: Charcot-Marie-Tooth disease type 1 (CMT1) is a group of autosomal dominantly inherited demyelinating sensorimotor neuropathies. Symptoms usually start in the first to second decade and include distal muscle weakness and wasting, sensory disturbances and foot deformities. The most frequent cause is a duplication of PMP22 whilst point mutations in PMP22 and other genes are rare causes.

Two novel pathogenic variants in KIAA1109 causing Alkuraya-Kučinskas syndrome in two Czech Roma brothers.

Recently described Alkuraya-Kučinskas syndrome (ALKKUCS) clinically presented with severe congenital hydrocephalus, severe brain hypoplasia and other multiple malformations has been described in only few families worldwide to date. ALKKUCS is caused by biallelic pathogenic variants in the KIAA1109 gene with autosomal recessive inheritance. We describe two brothers of Roma origin born with severe congenital hydrocephalus, brain hypoplasia and other clinical findings corresponding with ALKKUCS.

Prot2HG: a database of protein domains mapped to the human genome.

Genetic variation occurring within conserved functional protein domains warrants special attention when examining DNA variation in the context of disease causation. Here we introduce a resource, freely available at www.prot2hg.

Two types of recessive hereditary spastic paraplegia in Roma patients in compound heterozygous state; no ethnically prevalent variant found.

Hereditary spastic paraplegia (HSP or SPG) is a group of rare upper motor neuron diseases. As some ethnically-specific, disease-causing homozygous variants were described in the Czech Roma population, we hypotesised that some prevalent HSP-causing variant could exist in this population. Eight Czech Roma patients were found in a large group of Czech patients with suspected HSP and were tested using gene panel massively parallel sequencing (MPS).

Distinct patterns of complex rearrangements and a mutational signature of microhomeology are frequently observed in PLP1 copy number gain structural variants.

Background: We investigated the features of the genomic rearrangements in a cohort of 50 male individuals with proteolipid protein 1 (PLP1) copy number gain events who were ascertained with Pelizaeus-Merzbacher disease (PMD; MIM: 312080). We then compared our new data to previous structural variant mutagenesis studies involving the Xq22 region of the human genome. The aggregate data from 159 sequenced join-points (discontinuous sequences in the reference genome that are joined during the rearrangement process) were studied.

Moderate sensorineural hearing loss is typical for DFNB16 caused by various types of mutations affecting the STRC gene.

Introduction: Hearing loss is the most frequent sensory disorder and is genetically extremely heterogeneous. By far the most frequent cause of nonsyndromic autosomal recessive hearing loss (AR-NSHL) are biallelic pathogenic mutations in the GJB2 gene causing DFNB1. The worldwide search for the second most common type of AR-NSHL took almost two decades.

Loss of Neurological Disease HSAN-I-Associated Gene SPTLC2 Impairs CD8 T Cell Responses to Infection by Inhibiting T Cell Metabolic Fitness.

Patients with the neurological disorder HSAN-I suffer frequent infections, attributed to a lack of pain sensation and failure to seek care for minor injuries. Whether protective CD8 T cells are affected in HSAN-I patients remains unknown. Here, we report that HSAN-I-associated mutations in serine palmitoyltransferase subunit SPTLC2 dampened human T cell responses.