Bryant-Li-Bhoj syndrome (BLBS), which became OMIM-classified in 2022 (OMIM: 619720, 619721), is caused by germline variants in the two genes that encode histone H3.3 (H3-3A/H3F3A and H3-3B/H3F3B) [1-4]. This syndrome is characterized by developmental delay/intellectual disability, craniofacial anomalies, hyper/hypotonia, and abnormal neuroimaging [1, 5]. BLBS was initially categorized as a progressive neurodegenerative syndrome caused by de novo heterozygous variants in either H3-3A or H3-3B [1-4]. Here, we analyze the data of the 58 previously published individuals along 38 unpublished, unrelated individuals. In this larger cohort of 96 people, we identify causative missense, synonymous, and stop-loss variants. We also expand upon the phenotypic characterization by elaborating on the neurodevelopmental component of BLBS. Notably, phenotypic heterogeneity was present even amongst individuals harboring the same variant. To explore the complex phenotypic variation in this expanded cohort, the relationships between syndromic phenotypes with three variables of interest were interrogated: sex, gene containing the causative variant, and variant location in the H3.3 protein. While specific genotype-phenotype correlations have not been conclusively delineated, the results presented here suggest that the location of the variants within the H3.3 protein and the affected gene (H3-3A or H3-3B) contribute more to the severity of distinct phenotypes than sex. Since these variables do not account for all BLBS phenotypic variability, these findings suggest that additional factors may play a role in modifying the phenotypes of affected individuals. Histones are poised at the interface of genetics and epigenetics, highlighting the potential role for gene-environment interactions and the importance of future research.

• MeSH
• dítě MeSH
• dospělí MeSH
• fenotyp * MeSH
• histony * genetika   MeSH
• lidé MeSH
• mentální retardace genetika   patologie   MeSH
• mladiství MeSH
• neurodegenerativní nemoci genetika   patologie   MeSH
• neurovývojové poruchy genetika   patologie   MeSH
• předškolní dítě MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• histony * MeSH

• Publikační typ
• tisková chyba MeSH

Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50-deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function.

• Klíčová slova
• Development, Genetic diseases, Genetics, Neurodevelopment, iPS cells,
• MeSH
• enzymy opravy DNA genetika   MeSH
• genové regulační sítě MeSH
• jaderné proteiny genetika   MeSH
• lidé MeSH
• missense mutace MeSH
• neurovývojové poruchy * genetika   MeSH
• sestřih RNA MeSH
• sestřihové faktory genetika   MeSH
• spliceozomy * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• enzymy opravy DNA MeSH
• jaderné proteiny MeSH
• PRPF19 protein, human MeSH Prohlížeč
• sestřihové faktory MeSH

INTRODUCTION AND METHODS: We report two series of individuals with DDX3X variations, one (48 individuals) from physicians and one (44 individuals) from caregivers. RESULTS: These two series include several symptoms in common, with fairly similar distribution, which suggests that caregivers' data are close to physicians' data. For example, both series identified early childhood symptoms that were not previously described: feeding difficulties, mean walking age, and age at first words. DISCUSSION: Each of the two datasets provides complementary knowledge. We confirmed that symptoms are similar to those in the literature and provides more details on feeding difficulties. Caregivers considered that the symptom attention-deficit/hyperactivity disorder were most worrisome. Both series also reported sleep disturbance. Recently, anxiety has been reported in individuals with DDX3X variants. We strongly suggest that attention-deficit/hyperactivity disorder, anxiety, and sleep disorders need to be treated.

• Klíčová slova
• DDX3X, ADHD, caregivers, developmental milestones,
• MeSH
• DEAD-box RNA-helikasy MeSH
• hyperkinetická porucha * genetika   terapie   MeSH
• kojenec MeSH
• lidé MeSH
• osoby pečující o pacienty * MeSH
• předškolní dítě MeSH
• zpráva o sobě MeSH
• Check Tag
• kojenec MeSH
• lidé MeSH
• předškolní dítě MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• DDX3X protein, human MeSH Prohlížeč
• DEAD-box RNA-helikasy MeSH

BACKGROUND: Congenital myasthenic syndromes (CMSs) are characterized by hypotonia, episodic apnea, muscle weakness, ptosis and generalized fatigability. CMS type 20 (CMS20) is a rare disorder caused by variants in SLC5A7. In contrast to most other CMSs, CMS20 is also associated with neurodevelopmental disorders (NDDs). Only 19 patients from 14 families have been reported so far. METHODS: We studied a 12-year-old boy with symptoms manifested at six weeks of age. Later, he also showed speech delay, moderate intellectual disability and autism. Analysis of CMS genes known at the time of clinical diagnosis yielded no results. Trio exome sequencing (ES) was performed. RESULTS: ES revealed compound heterozygosity for two SLC5A7 variants, p.(Asn431Lys) and p.(Ile291Thr). While the first variant was absent from all databases, the second variant has already been described in one patient. In silico analysis of known pathogenic SLC5A7 variants showed that variants with a higher predicted deleteriousness may be associated with earlier onset and increased severity of neuromuscular manifestations. CONCLUSION: Our patient confirms that CMS20 can be associated with NDDs. The study illustrates the strength of ES in deciphering the genetic basis of rare diseases, contributes to characterization of CMS20 and suggests trends in genotype-phenotype correlation in CMS20.

• Klíčová slova
• SLC5A7, congenital myasthenic syndrome type 20, exome sequencing, neurodevelopmental disorders,
• MeSH
• genetické asociační studie MeSH
• heterozygot MeSH
• kongenitální myastenické syndromy * genetika   diagnóza   MeSH
• lidé MeSH
• mentální retardace * komplikace   MeSH
• missense mutace MeSH
• symportéry * genetika   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• SLC5A7 protein, human MeSH Prohlížeč
• symportéry * MeSH

PURPOSE: Proline Rich 12 (PRR12) is a gene of unknown function with suspected DNA-binding activity, expressed in developing mice and human brains. Predicted loss-of-function variants in this gene are extremely rare, indicating high intolerance of haploinsufficiency. METHODS: Three individuals with intellectual disability and iris anomalies and truncating de novo PRR12 variants were described previously. We add 21 individuals with similar PRR12 variants identified via matchmaking platforms, bringing the total number to 24. RESULTS: We observed 12 frameshift, 6 nonsense, 1 splice-site, and 2 missense variants and one patient with a gross deletion involving PRR12. Three individuals had additional genetic findings, possibly confounding the phenotype. All patients had developmental impairment. Variable structural eye defects were observed in 12/24 individuals (50%) including anophthalmia, microphthalmia, colobomas, optic nerve and iris abnormalities. Additional common features included hypotonia (61%), heart defects (52%), growth failure (54%), and kidney anomalies (35%). PrediXcan analysis showed that phecodes most strongly associated with reduced predicted PRR12 expression were enriched for eye- (7/30) and kidney- (4/30) phenotypes, such as wet macular degeneration and chronic kidney disease. CONCLUSION: These findings support PRR12 haploinsufficiency as a cause for a novel disorder with a wide clinical spectrum marked chiefly by neurodevelopmental and eye abnormalities.

• MeSH
• fenotyp MeSH
• haploinsuficience * genetika   MeSH
• lidé MeSH
• mentální retardace * genetika   MeSH
• missense mutace MeSH
• myši MeSH
• svalová hypotonie MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

The collapsin response mediator protein (CRMP) family proteins are intracellular mediators of neurotrophic factors regulating neurite structure/spine formation and are essential for dendrite patterning and directional axonal pathfinding during brain developmental processes. Among this family, CRMP5/DPYSL5 plays a significant role in neuronal migration, axonal guidance, dendrite outgrowth, and synapse formation by interacting with microtubules. Here, we report the identification of missense mutations in DPYSL5 in nine individuals with brain malformations, including corpus callosum agenesis and/or posterior fossa abnormalities, associated with variable degrees of intellectual disability. A recurrent de novo p.Glu41Lys variant was found in eight unrelated patients, and a p.Gly47Arg variant was identified in one individual from the first family reported with Ritscher-Schinzel syndrome. Functional analyses of the two missense mutations revealed impaired dendritic outgrowth processes in young developing hippocampal primary neuronal cultures. We further demonstrated that these mutations, both located in the same loop on the surface of DPYSL5 monomers and oligomers, reduced the interaction of DPYSL5 with neuronal cytoskeleton-associated proteins MAP2 and βIII-tubulin. Our findings collectively indicate that the p.Glu41Lys and p.Gly47Arg variants impair DPYSL5 function on dendritic outgrowth regulation by preventing the formation of the ternary complex with MAP2 and βIII-tubulin, ultimately leading to abnormal brain development. This study adds DPYSL5 to the list of genes implicated in brain malformation and in neurodevelopmental disorders.

• Klíčová slova
• DPYSL5, brain malformation, corpus callosum agenesis, de novo missense variants, dendrite branching, neurodevelopmental disorder, primary neuronal cultures,
• MeSH
• ageneze corpus callosum diagnostické zobrazování   genetika   MeSH
• dítě MeSH
• dospělí MeSH
• hydrolasy chemie   genetika   MeSH
• lidé MeSH
• mentální retardace diagnostické zobrazování   genetika   MeSH
• missense mutace genetika   MeSH
• mladý dospělý MeSH
• molekulární modely MeSH
• mozeček abnormality   diagnostické zobrazování   MeSH
• neurovývojové poruchy diagnostické zobrazování   genetika   MeSH
• předškolní dítě MeSH
• proteiny asociované s mikrotubuly chemie   genetika   metabolismus   MeSH
• tubulin metabolismus   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladý dospělý 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
• Názvy látek
• DPYSL5 protein, human MeSH Prohlížeč
• hydrolasy MeSH
• MAP2 protein, human MeSH Prohlížeč
• proteiny asociované s mikrotubuly MeSH
• TUBB3 protein, human MeSH Prohlížeč
• tubulin MeSH

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

• Publikační typ
• tisková chyba MeSH

Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case-control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E-06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E-07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype-genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.

• MeSH
• CCCTC-vazebný faktor genetika   MeSH
• DNA vazebné proteiny genetika   MeSH
• draslíkový kanál KCNQ3 genetika   MeSH
• genetická predispozice k nemoci * MeSH
• genetické asociační studie MeSH
• heterogenní jaderný ribonukleoprotein U genetika   MeSH
• kohortové studie MeSH
• lidé MeSH
• mutace MeSH
• mutační analýza DNA MeSH
• neurovývojové poruchy genetika   MeSH
• proteiny vázající RNA genetika   MeSH
• represorové proteiny genetika   MeSH
• studie případů a kontrol MeSH
• transkripční faktory bHLH genetika   MeSH
• transkripční faktory genetika   MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• CCCTC-vazebný faktor MeSH
• CTCF protein, human MeSH Prohlížeč
• DNA vazebné proteiny MeSH
• draslíkový kanál KCNQ3 MeSH
• heterogenní jaderný ribonukleoprotein U MeSH
• HNRNPU protein, human MeSH Prohlížeč
• KCNQ3 protein, human MeSH Prohlížeč
• LEO1 protein, human MeSH Prohlížeč
• proteiny vázající RNA MeSH
• represorové proteiny MeSH
• SPEN protein, human MeSH Prohlížeč
• TCF12 protein, human MeSH Prohlížeč
• transkripční faktory bHLH MeSH
• transkripční faktory MeSH
• ZBTB18 protein, human MeSH Prohlížeč

• MeSH
• dyskineze diagnóza   genetika   MeSH
• epilepsie diagnóza   genetika   MeSH
• lidé MeSH
• mutace genetika   MeSH
• nádorové supresorové proteiny genetika   MeSH
• proteiny vázající GTP genetika   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• dopisy MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• nádorové supresorové proteiny MeSH
• proteiny vázající GTP MeSH
• RHOBTB2 protein, human MeSH Prohlížeč