BACKGROUND: Heterozygous loss-of-function variants in CHD8 have been associated with a syndromic neurodevelopmental-disease spectrum, collectively referred to as CHD8-related neurodevelopmental disorders. Several different clinical manifestations, affecting neurodevelopmental and systemic domains, have been described, presenting with highly variable expressivity. Some expressions are well established and comprise autism spectrum disorders, psychomotor delay with cognitive impairment, postnatal overgrowth with macrocephaly, structural brain abnormalities, gastrointestinal disturbances, and behavioral and sleep-pattern problems. However, the complete phenotypic spectrum of CHD8-related disorders is still undefined. In 2021, our group described two singular female patients with CHD8-related neurodevelopmental disorder and striking dystonic manifestations, prompting the suggestion that dystonia should be considered a possible component of this condition. CASE SERIES PRESENTATION: We describe three additional unrelated female individuals, each carrying a different CHD8 frameshift variant and whose clinical presentations were primarily characterized by young-onset dystonia. Their dystonic manifestations were remarkably heterogeneous and ranged from focal, exercise-dependent, apparently isolated forms to generalized permanent phenotypes accompanied by spasticity and tremor. Neurocognitive impairment and autistic behaviors, typical of CHD8-related disorders, were virtually absent or at the mild end of the spectrum. CONCLUSIONS: This work validates our previous observation that dystonia is part of the phenotypic spectrum of CHD8-related neurodevelopmental disorders with potential female preponderance, raising new challenges and opportunities in the diagnosis and management of this condition. It also highlights the importance of in-depth neurologic phenotyping of patients carrying variants associated with neurodevelopmental disorders, as the connection between neurodevelopmental and movement disorders is proving closer than previously appreciated.

• MeSH
• Child MeSH
• DNA-Binding Proteins * genetics   MeSH
• Adult MeSH
• Dystonic Disorders genetics   diagnosis   physiopathology   complications   MeSH
• Dystonia genetics   etiology   physiopathology   diagnosis   MeSH
• Phenotype * MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Neurodevelopmental Disorders genetics   diagnosis   MeSH
• Frameshift Mutation MeSH
• Child, Preschool MeSH
• Transcription Factors genetics   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH

The chicken Tva cell surface protein, a member of the low-density lipoprotein receptor family, has been identified as an entry receptor for avian leukosis virus of classic subgroup A and newly emerging subgroup K. Because both viruses represent an important concern for the poultry industry, we introduced a frame-shifting deletion into the chicken tva locus with the aim of knocking-out Tva expression and creating a virus-resistant chicken line. The tva knock-out was prepared by CRISPR/Cas9 gene editing in chicken primordial germ cells and orthotopic transplantation of edited cells into the testes of sterilized recipient roosters. The resulting tva -/- chickens tested fully resistant to avian leukosis virus subgroups A and K, both in in vitro and in vivo assays, in contrast to their susceptible tva +/+ and tva +/- siblings. We also found a specific disorder of the cobalamin/vitamin B12 metabolism in the tva knock-out chickens, which is in accordance with the recently recognized physiological function of Tva as a receptor for cobalamin in complex with transcobalamin transporter. Last but not least, we bring a new example of the de novo resistance created by CRISPR/Cas9 editing of pathogen dependence genes in farm animals and, furthermore, a new example of gene editing in chicken.

• MeSH
• Gene Editing MeSH
• Gene Knockout Techniques MeSH
• Chickens virology   MeSH
• Chick Embryo MeSH
• Methylmalonic Acid blood   MeSH
• Frameshift Mutation MeSH
• Avian Proteins genetics   physiology   MeSH
• Receptors, Virus genetics   physiology   MeSH
• Avian Leukosis Virus classification   physiology   MeSH
• Vitamin B 12 metabolism   MeSH
• Animals MeSH
• Check Tag
• Chick Embryo MeSH
• Male MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Intragenic rearrangements and sequence variants in the calmodulin-binding transcription activator 1 gene (CAMTA1) can result in a spectrum of clinical presentations, most notably congenital ataxia with or without intellectual disability. We describe for the first time a myoclonic dystonia-predominant phenotype associated with a novel CAMTA1 sequence variant. Furthermore, by identifying an additional, recurrent CAMTA1 sequence variant in an individual with a more typical neurodevelopmental disease manifestation, we contribute to the elucidation of phenotypic variability associated with CAMTA1 gene mutations.

• MeSH
• Adult MeSH
• Dystonic Disorders genetics   MeSH
• Phenotype MeSH
• Genetic Association Studies MeSH
• Humans MeSH
• Intellectual Disability genetics   MeSH
• Hearing Loss genetics   MeSH
• Codon, Nonsense * MeSH
• Vision Disorders genetics   MeSH
• Frameshift Mutation * MeSH
• Child, Preschool MeSH
• Calcium-Binding Proteins genetics   MeSH
• Pedigree MeSH
• Sequence Deletion * MeSH
• Exome Sequencing MeSH
• Trans-Activators genetics   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH

• MeSH
• Clone Cells MeSH
• K562 Cells MeSH
• CRISPR-Cas Systems MeSH
• Gene Knockout Techniques MeSH
• Homozygote MeSH
• Hyperhomocysteinemia drug therapy   genetics   MeSH
• Cells, Cultured MeSH
• Folic Acid therapeutic use   MeSH
• Humans MeSH
• Anemia, Megaloblastic drug therapy   genetics   MeSH
• Adolescent MeSH
• Frameshift Mutation MeSH
• Recurrence MeSH
• Sequence Deletion MeSH
• Exome Sequencing MeSH
• Sodium-Hydrogen Exchanger 1 deficiency   genetics   MeSH
• Vitamin B 12 therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Publication type
• Letter MeSH
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH

Pathogenic sequence variants in the IQ motif- and Sec7 domain-containing protein 2 (IQSEC2) gene have been confirmed as causative in the aetiopathogenesis of neurodevelopmental disorders (intellectual disability, autism) and epilepsy. We report on a case of a family with three sons; two of them manifest delayed psychomotor development and epilepsy. Initially proband A was examined using a multistep molecular diagnostics algorithm, including karyotype and array-comparative genomic hybridization analysis, both with negative results. Therefore, probands A and B and their unaffected parents were enrolled for an analysis using targeted "next-generation" sequencing (NGS) with a gene panel ClearSeq Inherited DiseaseXT (Agilent Technologies) and verification analysis by Sanger sequencing. A novel frameshift variant in the X-linked IQSEC2 gene NM_001111125.2:c.1813_1814del, p.(Asp605Profs*3) on protein level, was identified in both affected probands and their asymptomatic mother, having skewed X chromosome inactivation (XCI) (100:0). As the IQSEC2 gene is a known gene escaping from XCI in humans, we expect the existence of mechanisms maintaining the normal or enough level of the IQSEC2 protein in the asymptomatic mother. Further analyses may help to the characterization of the presented novel frameshift variant in the IQSEC2 gene as well as to elucidate the mechanisms leading to the rare asymptomatic phenotypes in females.

• MeSH
• Algorithms MeSH
• Gene Deletion MeSH
• Child MeSH
• Epilepsy complications   genetics   MeSH
• Phenotype MeSH
• Genetic Variation * MeSH
• X Chromosome Inactivation MeSH
• Karyotyping MeSH
• Humans MeSH
• Neurodevelopmental Disorders complications   genetics   MeSH
• Frameshift Mutation MeSH
• Child, Preschool MeSH
• Chromosome Banding MeSH
• Oligonucleotide Array Sequence Analysis MeSH
• Comparative Genomic Hybridization * MeSH
• Guanine Nucleotide Exchange Factors genetics   MeSH
• High-Throughput Nucleotide Sequencing MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH

Intracellular accumulation of misfolded proteins causes toxic proteinopathies, diseases without targeted therapies. Mucin 1 kidney disease (MKD) results from a frameshift mutation in the MUC1 gene (MUC1-fs). Here, we show that MKD is a toxic proteinopathy. Intracellular MUC1-fs accumulation activated the ATF6 unfolded protein response (UPR) branch. We identified BRD4780, a small molecule that clears MUC1-fs from patient cells, from kidneys of knockin mice and from patient kidney organoids. MUC1-fs is trapped in TMED9 cargo receptor-containing vesicles of the early secretory pathway. BRD4780 binds TMED9, releases MUC1-fs, and re-routes it for lysosomal degradation, an effect phenocopied by TMED9 deletion. Our findings reveal BRD4780 as a promising lead for the treatment of MKD and other toxic proteinopathies. Generally, we elucidate a novel mechanism for the entrapment of misfolded proteins by cargo receptors and a strategy for their release and anterograde trafficking to the lysosome.

• MeSH
• Benzamides chemistry   metabolism   pharmacology   MeSH
• Epithelial Cells cytology   metabolism   MeSH
• Imidazoline Receptors antagonists & inhibitors   genetics   metabolism   MeSH
• Induced Pluripotent Stem Cells cytology   metabolism   MeSH
• Kidney cytology   metabolism   pathology   MeSH
• Humans MeSH
• Lysosomes metabolism   MeSH
• RNA, Small Interfering metabolism   MeSH
• Mucin-1 chemistry   genetics   metabolism   MeSH
• Mice, Transgenic MeSH
• Mice MeSH
• Kidney Diseases metabolism   pathology   MeSH
• Frameshift Mutation MeSH
• RNA Interference MeSH
• Unfolded Protein Response drug effects   MeSH
• Activating Transcription Factor 6 metabolism   MeSH
• Vesicular Transport Proteins chemistry   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

De novo sequence variants, including truncating and splicing variants, in the additional sex‑combs like 3 gene (ASXL3) have been described as the cause of Bainbridge‑Ropers syndrome (BRS). This pathology is characterized by delayed psychomotor development, severe intellectual disability, growth delay, hypotonia and facial dimorphism. The present study reports a case of a girl (born in 2013) with severe global developmental delay, central hypotonia, microcephaly and poor speech. The proband was examined using a multi‑step molecular diagnostics algorithm, including karyotype and array‑comparative genomic hybridization analysis, with negative results. Therefore, the proband and her unaffected parents were enrolled for a pilot study using targeted next‑generation sequencing technology (NGS) with gene panel ClearSeq Inherited DiseaseXT and subsequent validation by Sanger sequencing. A novel de novo heterozygous frameshift variant in the ASXL3 gene (c.3006delT, p.R1004Efs*21), predicted to result in a premature termination codon, was identified. In conclusion, the present study demonstrated that targeted NGS using a suitable, gene‑rich panel may provide a conclusive molecular genetics diagnosis in children with severe global developmental delays.

• MeSH
• Child MeSH
• Humans MeSH
• Microcephaly genetics   MeSH
• Pilot Projects MeSH
• Speech Disorders genetics   MeSH
• Frameshift Mutation MeSH
• Pedigree MeSH
• Muscle Hypotonia genetics   MeSH
• Transcription Factors genetics   MeSH
• Developmental Disabilities genetics   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH

Calcium/calmodulin-dependent protein kinases (CaMKs) are key mediators of calcium signaling and underpin neuronal health. Although widely studied, the contribution of CaMKs to Mendelian disease is rather enigmatic. Here, we describe an unusual neurodevelopmental phenotype, characterized by milestone delay, intellectual disability, autism, ataxia, and mixed hyperkinetic movement disorder including severe generalized dystonia, in a proband who remained etiologically undiagnosed despite exhaustive testing. We performed trio whole-exome sequencing to identify a de novo essential splice-site variant (c.981+1G>A) in CAMK4, encoding CaMKIV. Through in silico evaluation and cDNA analyses, we demonstrated that c.981+1G>A alters CAMK4 pre-mRNA processing and results in a stable mRNA transcript containing a 77-nt out-of-frame deletion and a premature termination codon within the last exon. The expected protein, p.Lys303Serfs*28, exhibits selective loss of the carboxy-terminal regulatory domain of CaMKIV and bears striking structural resemblance to previously reported synthetic mutants that confer constitutive CaMKIV activity. Biochemical studies in proband-derived cells confirmed an activating effect of c.981+1G>A and indicated that variant-induced excessive CaMKIV signaling is sensitive to pharmacological manipulation. Additionally, we found that variants predicted to cause selective depletion of CaMKIV's regulatory domain are unobserved in diverse catalogs of human variation, thus revealing that c.981+1G>A is a unique molecular event. We propose that our proband's phenotype is explainable by a dominant CAMK4 splice-disrupting mutation that acts through a gain-of-function mechanism. Our findings highlight the importance of CAMK4 in human neurodevelopment, provide a foundation for future clinical research of CAMK4, and suggest the CaMKIV signaling pathway as a potential drug target in neurological disease.

• MeSH
• Gain of Function Mutation genetics   MeSH
• Cerebellar Ataxia genetics   MeSH
• Exome MeSH
• Exons genetics   MeSH
• Phenotype MeSH
• Hyperkinesis genetics   MeSH
• Humans MeSH
• Intellectual Disability genetics   MeSH
• Mutation MeSH
• Codon, Nonsense genetics   MeSH
• Frameshift Mutation genetics   MeSH
• Calcium-Calmodulin-Dependent Protein Kinase Type 4 genetics   metabolism   MeSH
• Pedigree MeSH
• Exome Sequencing MeSH
• RNA Splicing genetics   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH

Recently, the genetic cause of several syndromic forms of glycemia dysregulation has been described. One of them, MEHMO syndrome, is a rare X-linked syndrome recently linked to the EIF2S3 gene mutations. MEHMO is characterized by Mental retardation, Epilepsy, Hypogonadism/hypogenitalism, Microcephaly, and Obesity. Moreover, patients with MEHMO had also diabetes and endocrine phenotype, but detailed information is missing. We aimed to provide more details on the endocrine phenotype in two previously reported male probands with MEHMO carrying a frame-shift mutation (I465fs) in the EIF2S3 gene. Both probands had a neonatal hypoglycemia, early onset insulin-dependent diabetes, and hypopituitarism due to dysregulation and gradual decline of peptide hormone secretion. Based on the clinical course in our two probands and also in previously published patients, neonatal hypoglycemia followed by early-onset diabetes and hypopituitarism may be a consistent part of the MEHMO phenotype.

• MeSH
• Diabetes Mellitus, Type 1 congenital   genetics   MeSH
• Endocrine Glands metabolism   MeSH
• Epilepsy genetics   MeSH
• Eukaryotic Initiation Factor-2 genetics   MeSH
• Phenotype MeSH
• Hypoglycemia congenital   genetics   MeSH
• Hypogonadism genetics   MeSH
• Hypopituitarism congenital   genetics   MeSH
• Humans MeSH
• X-Linked Intellectual Disability genetics   MeSH
• Microcephaly genetics   MeSH
• Infant, Newborn MeSH
• Obesity genetics   MeSH
• Genitalia abnormalities   MeSH
• Frameshift Mutation MeSH
• Transcription Factors MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Infant, Newborn MeSH
• Publication type
• Journal Article MeSH

Chřipkové viry se vyskytují celosvětově. Ročně jimi onemocní v průměru 10 až 20 % populace. V důsledku toho zemře 250 000 až 500 000 pacientů ročně. Tato čísla by mohla být daleko nižší, kdyby lidé chřipkové infekce nepodceňovali a nezanedbávali prevenci. O to smutnější je fakt, že máme k dispozici vakcínu, tzn. vysoce účinný preventivní nástroj. Světová zdravotnická organizace (WHO) doporučuje 30% proočkovanost populace - Spojené státy dosahují podle CDC 46,8 % v rámci celé populace (nad šest měsíců věku), zatímco česká populace se pohybuje okolo pouhých 6 %. Alespoň částečnou odpověď na otázku, proč tomu tak je, se snaží nalézt následující text.

Influenza virus causes significant morbidity worldwide each year; ten to twenty percent people are infected. Based on current estimates, the influenza associated deaths range between 250,000 to 500,000 annually. Many of these preventable influenza-associated deaths result from underestimation of the influenza infection and common misconceptions about the benefits of the most effective method for influenza prevention - the influenza vaccine. WHO recommends 30% vaccination coverage. While in the United States of America the vaccination coverage reaches 46,8 % of population, in the Czech Republic the immunization coverage reaches only six percent of the population. The following commentary may provide some answers.

• MeSH
• Influenza, Human * pathology   therapy   virology   MeSH
• Epidemics MeSH
• Genetic Drift MeSH
• Orthomyxoviridae Infections * complications   pathology   prevention & control   MeSH
• Humans MeSH
• Vaccination Refusal MeSH
• Orthomyxoviridae * genetics   classification   pathogenicity   MeSH
• Patient Acceptance of Health Care MeSH
• Pandemics MeSH
• Health Promotion MeSH
• Frameshift Mutation MeSH
• Risk Factors MeSH
• Influenza Vaccines * economics   classification   therapeutic use   MeSH
• Health Personnel MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH
• Geographicals
• Czech Republic MeSH
• United States MeSH