Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize type I interferons (IFNs)1,2, conferring a predisposition to life-threatening COVID-19 pneumonia3. Here we report that patients with autosomal recessive NIK or RELB deficiency, or a specific type of autosomal-dominant NF-κB2 deficiency, also have neutralizing autoantibodies against type I IFNs and are at higher risk of getting life-threatening COVID-19 pneumonia. In patients with autosomal-dominant NF-κB2 deficiency, these autoantibodies are found only in individuals who are heterozygous for variants associated with both transcription (p52 activity) loss of function (LOF) due to impaired p100 processing to generate p52, and regulatory (IκBδ activity) gain of function (GOF) due to the accumulation of unprocessed p100, therefore increasing the inhibitory activity of IκBδ (hereafter, p52LOF/IκBδGOF). By contrast, neutralizing autoantibodies against type I IFNs are not found in individuals who are heterozygous for NFKB2 variants causing haploinsufficiency of p100 and p52 (hereafter, p52LOF/IκBδLOF) or gain-of-function of p52 (hereafter, p52GOF/IκBδLOF). In contrast to patients with APS-1, patients with disorders of NIK, RELB or NF-κB2 have very few tissue-specific autoantibodies. However, their thymuses have an abnormal structure, with few AIRE-expressing medullary thymic epithelial cells. Human inborn errors of the alternative NF-κB pathway impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases.

• MeSH
• aktivační mutace MeSH
• autoprotilátky * imunologie   MeSH
• COVID-19 genetika   imunologie   MeSH
• epiteliální buňky štítné žlázy metabolismus   patologie   MeSH
• genetická predispozice k nemoci * MeSH
• heterozygot MeSH
• interferon typ I * antagonisté a inhibitory   imunologie   MeSH
• kinasa indukující NF-kappaB MeSH
• lidé MeSH
• mutace ztráty funkce MeSH
• NF-kappa B - podjednotka p52 nedostatek   genetika   MeSH
• NF-kappa B * nedostatek   genetika   MeSH
• protein AIRE MeSH
• proteiny I-kappa B nedostatek   genetika   MeSH
• thymus abnormality   imunologie   patologie   MeSH
• virová pneumonie genetika   imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Nuclear deubiquitinase BAP1 (BRCA1-associated protein 1) is a core component of multiprotein complexes that promote transcription by reversing the ubiquitination of histone 2A (H2A). BAP1 is a tumor suppressor whose germline loss-of-function variants predispose to cancer. To our knowledge, there are very rare examples of different germline variants in the same gene causing either a neurodevelopmental disorder (NDD) or a tumor predisposition syndrome. Here, we report a series of 11 de novo germline heterozygous missense BAP1 variants associated with a rare syndromic NDD. Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. In T cells isolated from two affected children, H2A deubiquitination was impaired. In matching peripheral blood mononuclear cells, histone H3 K27 acetylation ChIP-seq indicated that these BAP1 variants induced genome-wide chromatin state alterations, with enrichment for regulatory regions surrounding genes of the ubiquitin-proteasome system (UPS). Altogether, these results define a clinical syndrome caused by rare germline missense BAP1 variants that alter chromatin remodeling through abnormal histone ubiquitination and lead to transcriptional dysregulation of developmental genes.

• MeSH
• chromatin chemie   imunologie   MeSH
• dítě MeSH
• faktor C1 hostitelské buňky genetika   imunologie   MeSH
• heterozygot MeSH
• histony genetika   imunologie   MeSH
• kojenec MeSH
• lidé MeSH
• missense mutace * MeSH
• mladiství MeSH
• mutace ztráty funkce * MeSH
• nádorové supresorové proteiny nedostatek   genetika   imunologie   MeSH
• neurovývojové poruchy genetika   imunologie   patologie   MeSH
• předškolní dítě MeSH
• proteasomový endopeptidasový komplex genetika   imunologie   MeSH
• protein BRCA1 genetika   imunologie   MeSH
• regulace genové exprese MeSH
• restrukturace chromatinu genetika   imunologie   MeSH
• rodina MeSH
• T-lymfocyty imunologie   patologie   MeSH
• thiolesterasa ubikvitinu nedostatek   genetika   imunologie   MeSH
• ubikvitin genetika   imunologie   MeSH
• ubikvitinace MeSH
• ubikvitinligasy genetika   imunologie   MeSH
• zárodečné mutace * MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

DDX3X is a ubiquitously expressed RNA helicase involved in multiple stages of RNA biogenesis. DDX3X is frequently mutated in Burkitt lymphoma, but the functional basis for this is unknown. Here, we show that loss-of-function DDX3X mutations are also enriched in MYC-translocated diffuse large B cell lymphoma and reveal functional cooperation between mutant DDX3X and MYC. DDX3X promotes the translation of mRNA encoding components of the core translational machinery, thereby driving global protein synthesis. Loss-of-function DDX3X mutations moderate MYC-driven global protein synthesis, thereby buffering MYC-induced proteotoxic stress during early lymphomagenesis. Established lymphoma cells restore full protein synthetic capacity by aberrant expression of DDX3Y, a Y chromosome homolog, the expression of which is normally restricted to the testis. These findings show that DDX3X loss of function can buffer MYC-driven proteotoxic stress and highlight the capacity of male B cell lymphomas to then compensate for this loss by ectopic DDX3Y expression.

• MeSH
• B-buněčný lymfom enzymologie   genetika   patologie   MeSH
• B-lymfocyty enzymologie   patologie   MeSH
• DEAD-box RNA-helikasy genetika   metabolismus   MeSH
• dítě MeSH
• dospělí MeSH
• homeostáze proteinů MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mutace ztráty funkce MeSH
• myši transgenní MeSH
• nádorové buněčné linie MeSH
• nádorové proteiny biosyntéza   genetika   MeSH
• předškolní dítě MeSH
• proteom MeSH
• proteosyntéza MeSH
• protoonkogenní proteiny c-myc genetika   metabolismus   MeSH
• regulace genové exprese enzymů MeSH
• regulace genové exprese u nádorů MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• stres endoplazmatického retikula MeSH
• vedlejší histokompatibilní antigeny genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

ZEB1 loss-of-function (LoF) alleles are known to cause a rare autosomal dominant disorder-posterior polymorphous corneal dystrophy type 3 (PPCD3). To date, 50 pathogenic LoF variants have been identified as disease-causing and familial studies have indicated that the PPCD3 phenotype is penetrant in approximately 95% of carriers. In this study, we interrogated in-house exomes (n = 3616) and genomes (n = 88) for the presence of putative heterozygous LoF variants in ZEB1. Next, we performed detailed phenotyping in a father and his son who carried a novel LoF c.1279C>T; p.(Glu427*) variant in ZEB1 (NM_030751.6) absent from the gnomAD v.2.1.1 dataset. Ocular examination of the two subjects did not show any abnormalities characteristic of PPCD3. GnomAD (n = 141,456 subjects) was also interrogated for LoF ZEB1 variants, notably 8 distinct heterozygous changes presumed to lead to ZEB1 haploinsufficiency, not reported to be associated with PPCD3, have been identified. The NM_030751.6 transcript has a pLI score ≥ 0.99, indicating extreme intolerance to haploinsufficiency. In conclusion, ZEB1 LoF variants are present in a general population at an extremely low frequency. As PPCD3 can be asymptomatic, the true penetrance of ZEB1 LoF variants remains currently unknown but is likely to be lower than estimated by the familial led approaches adopted to date.

• MeSH
• dědičné dystrofie rohovky genetika   patologie   MeSH
• haploinsuficience MeSH
• heterozygot MeSH
• kultivované buňky MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace ztráty funkce * MeSH
• penetrance * MeSH
• rodokmen MeSH
• transkripční faktor Zeb1 genetika   metabolismus   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH

Congenital heart disease is the most common type of birth defect, accounting for one-third of all congenital anomalies. Using whole-exome sequencing of 2718 patients with congenital heart disease and a search in GeneMatcher, we identified 30 patients from 21 unrelated families of different ancestries with biallelic phospholipase D1 (PLD1) variants who presented predominantly with congenital cardiac valve defects. We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy. Furthermore, we established that p.I668F is a founder variant among Ashkenazi Jews (allele frequency of ~2%) and describe the phenotypic spectrum of PLD1-associated congenital heart defects. PLD1 missense variants were overrepresented in regions of the protein critical for catalytic activity, and, correspondingly, we observed a strong reduction in enzymatic activity for most of the mutant proteins in an enzymatic assay. Finally, we demonstrate that PLD1 inhibition decreased endothelial-mesenchymal transition, an established pivotal early step in valvulogenesis. In conclusion, our study provides a more detailed understanding of disease mechanisms and phenotypic expression associated with PLD1 loss of function.

• MeSH
• alely * MeSH
• fosfolipasa D * genetika   metabolismus   MeSH
• lidé MeSH
• mutace ztráty funkce * MeSH
• nemoci srdečních chlopní * enzymologie   genetika   MeSH
• vrozené srdeční vady * enzymologie   genetika   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

Cullin 4B (CUL4B), lysosomal-associated membrane protein Type 2 (LAMP2), ATP1B4, TMEM255A, and ZBTB33 are neighboring genes on Xq24. Mutations in CUL4B result in Cabezas syndrome (CS). Male CS patients present with dysmorphic, neuropsychiatric, genitourinary, and endocrine abnormalities. Heterozygous CS females are clinically asymptomatic. LAMP2 mutations cause Danon disease (DD). Cardiomyopathy is a dominant feature of DD present in both males and heterozygous females. No monogenic phenotypes have been associated with mutations in ATP1B4, TMEM255A, and ZBTB33 genes. To facilitate diagnostics and counseling in CS and DD families, we present a female DD patient with a de novo Alu-mediated Xq24 rearrangement causing a deletion encompassing CUL4B, LAMP2, and also the other three neighboring genes. Typical to females heterozygous for CUL4B mutations, the patient was CS asymptomatic, however, presented with extremely skewed X-chromosome inactivation (XCI) ratios in peripheral white blood cells. As a result of the likely selection against CUL4B deficient clones, only minimal populations (~3%) of LAMP2 deficient leukocytes were identified by flow cytometry. On the contrary, myocardial LAMP2 protein expression suggested random XCI. We demonstrate that contiguous CUL4B and LAMP2 loss-of-function copy number variations occur and speculate that male patients carrying similar defects could present with features of both CS and DD.

• MeSH
• chromozomální delece MeSH
• dospělí MeSH
• elementy Alu genetika   MeSH
• exony genetika   MeSH
• glykogenóza typu IIb diagnóza   genetika   patofyziologie   MeSH
• inaktivace chromozomu X genetika   MeSH
• kardiomyopatie genetika   patofyziologie   MeSH
• kulinové proteiny genetika   MeSH
• lidé MeSH
• membránový protein 2 asociovaný s lyzozomy genetika   MeSH
• mentální retardace vázaná na chromozom X genetika   patofyziologie   MeSH
• mutace ztráty funkce genetika   MeSH
• myokard metabolismus   MeSH
• sodíko-draslíková ATPasa genetika   MeSH
• transkripční faktory genetika   MeSH
• variabilita počtu kopií segmentů DNA genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH

TDP2 encodes a 5'-tyrosyl DNA phosphodiesterase required for the efficient repair of double-strand breaks (DSBs) induced by the abortive activity of DNA topoisomerase II (TOP2). To date, only three homozygous variants in TDP2 have been reported in six patients from four unrelated pedigrees with spinocerebellar ataxia 23 (SCAR23). By whole-exome sequencing, we identified a novel TDP2 splice-site variant (c.636 + 3_636 + 6del) in two Italian siblings (aged 40 and 45) showing progressive ataxia, intellectual disability, speech delay, refractory seizures, and various physical anomalies. The variant caused exon 5 skipping with consequent nonsense-mediated mRNA decay and defective repair of TOP2-induced DSBs, as demonstrated by the functional assays on the patients' fibroblasts. Our findings further demonstrate the pathogenic role of TDP2 biallelic loss-of-function variants in SCAR23 pathogenesis. Considering the age of our patients, the oldest reported to date, and their extensive follow-up, our study delineates in more detail the clinical phenotype related to the loss of TDP2 activity.

• MeSH
• DNA vazebné proteiny genetika   MeSH
• dospělí MeSH
• fosfodiesterasy genetika   MeSH
• geny recesivní genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mentální retardace genetika   patologie   MeSH
• mutace ztráty funkce genetika   MeSH
• spinocerebelární ataxie genetika   patofyziologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein with tyrosine-kinase signaling activity, involved in many cellular functions including cell growth and differentiation. Germ line loss-of-function mutations in EGFR lead to a severe neonatal skin disorder (Online Mendelian Inheritance in Man #131550). We report 18 premature Roma children from 16 families with birthweights ranging 440-1470 g and multisystem diseases due to the homozygous mutation c.1283G˃A (p.Gly428Asp) in EGFR. They presented with thin, translucent, fragile skin (14/15), skin desquamation (10/17), ichthyosis (9/17), recurrent skin infections and sepsis (9/12), nephromegaly (10/16) and congenital heart defects (7/17). Their prognosis was poor, and all died before the age of 6 months except one 13-year-old boy with a severe skin disorder, dentinogenesis imperfecta, Fanconi-like syndrome and secondary hyperaldosteronism. Management of ion and water imbalances and extremely demanding skin care may improve the unfavorable outcome of such patients.

• MeSH
• dentinogenesis imperfecta diagnóza   genetika   mortalita   MeSH
• dítě MeSH
• erbB receptory nedostatek   genetika   MeSH
• homozygot MeSH
• ichtyóza diagnóza   genetika   mortalita   MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mutace ztráty funkce MeSH
• nemoci ledvin vrozené   diagnóza   genetika   mortalita   MeSH
• novorozenec nedonošený MeSH
• novorozenec s velmi nízkou porodní hmotností MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• Romové genetika   MeSH
• sekvenování exomu MeSH
• stupeň závažnosti nemoci MeSH
• syndrom MeSH
• vrozené srdeční vady diagnóza   genetika   mortalita   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• Geografické názvy
• Česká republika MeSH
• Slovenská republika MeSH

The most common histological subtypes of cutaneous melanoma include superficial spreading and nodular melanoma. However, the spectrum of somatic mutations developed in those lesions and all potential druggable targets have not yet been fully elucidated. We present the results of a sequence capture NGS analysis of 114 primary nodular and superficial spreading melanomas identifying driver mutations using biostatistical, immunohistochemical and/or functional approach. The spectrum and frequency of pathogenic or likely pathogenic variants were identified across 54 evaluated genes, including 59 novel mutations, and the newly identified TP53 loss-of-function mutations p.(L194P) and p.(R280K). Frequently mutated genes most commonly affected the MAPK pathway, followed by chromatin remodeling, and cell cycle regulation. Frequent aberrations were also detected in the genes coding for proteins involved in DNA repair and the regulation and modification of cellular tight junctions. Furthermore, relatively frequent mutations were described in KDR and MET, which represent potential clinically important targets. Those results suggest that with the development of new therapeutic possibilities, not only BRAF testing, but complex molecular testing of cutaneous melanoma may become an integral part of the decision process concerning the treatment of patients with melanoma.

• MeSH
• buněčný cyklus genetika   MeSH
• dospělí MeSH
• frekvence genu genetika   MeSH
• genetická predispozice k nemoci genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• MAP kinasový signální systém genetika   MeSH
• melanom genetika   patologie   MeSH
• mladý dospělý MeSH
• mutace ztráty funkce genetika   MeSH
• nádorové biomarkery genetika   MeSH
• nádorový supresorový protein p53 genetika   MeSH
• nádory kůže genetika   patologie   MeSH
• oprava DNA genetika   MeSH
• protoonkogenní proteiny B-raf genetika   MeSH
• restrukturace chromatinu genetika   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• těsný spoj genetika   MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

PURPOSE: To define the phenotypic and mutational spectrum of epilepsies related to DEPDC5, NPRL2 and NPRL3 genes encoding the GATOR1 complex, a negative regulator of the mTORC1 pathway METHODS: We analyzed clinical and genetic data of 73 novel probands (familial and sporadic) with epilepsy-related variants in GATOR1-encoding genes and proposed new guidelines for clinical interpretation of GATOR1 variants. RESULTS: The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g., hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4 years, often sleep-related and drug-resistant (54%), and associated with focal cortical dysplasia (20%). Infantile spasms were reported in 10% of the probands. Sudden unexpected death in epilepsy (SUDEP) occurred in 10% of the families. Novel classification framework of all 140 epilepsy-related GATOR1 variants (including the variants of this study) revealed that 68% are loss-of-function pathogenic, 14% are likely pathogenic, 15% are variants of uncertain significance and 3% are likely benign. CONCLUSION: Our data emphasize the increasingly important role of GATOR1 genes in the pathogenesis of focal epilepsies (>180 probands to date). The GATOR1 phenotypic spectrum ranges from sporadic early-onset epilepsies with cognitive impairment comorbidities to familial focal epilepsies, and SUDEP.

• MeSH
• Brugadův syndrom genetika   mortalita   patofyziologie   MeSH
• dítě MeSH
• epilepsie komplikace   epidemiologie   genetika   patofyziologie   MeSH
• genetická predispozice k nemoci MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mTORC1 genetika   MeSH
• multiproteinové komplexy genetika   MeSH
• mutace INDEL genetika   MeSH
• mutace ztráty funkce genetika   MeSH
• nádorové supresorové proteiny genetika   MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• proteiny aktivující GTPasu genetika   MeSH
• represorové proteiny genetika   MeSH
• rodokmen MeSH
• signální transdukce genetika   MeSH
• variabilita počtu kopií segmentů DNA genetika   MeSH
• záchvaty komplikace   epidemiologie   genetika   patofyziologie   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH