RESUMO
Craniofacial phenotyping is critical for both syndrome delineation and diagnosis because craniofacial abnormalities occur in 30% of characterized genetic syndromes. Clinical reports, textbooks, and available software tools typically provide two-dimensional, static images and illustrations of the characteristic phenotypes of genetic syndromes. In this work, we provide an interactive web application that provides three-dimensional, dynamic visualizations for the characteristic craniofacial effects of 95 syndromes. Users can visualize syndrome facial appearance estimates quantified from data and easily compare craniofacial phenotypes of different syndromes. Our application also provides a map of morphological similarity between a target syndrome and other syndromes. Finally, users can upload 3D facial scans of individuals and compare them to our syndrome atlas estimates. In summary, we provide an interactive reference for the craniofacial phenotypes of syndromes that allows for precise, individual-specific comparisons of dysmorphology.
Assuntos
Face , Software , Humanos , Fácies , Fenótipo , SíndromeRESUMO
Mammalian SWI/SNF complexes are multi-subunit chromatin remodeling complexes associated with an ATPase (either SMARCA4 or SMARCA2). Heterozygous mutations in the SMARCA2 ATPase cause Nicolaides-Baraitser syndrome (NCBRS), an intellectual disability syndrome associated with delayed speech onset. We engineered human embryonic stem cells (hESCs) to carry NCBRS-associated heterozygous SMARCA2 K755R or R1159Q mutations. While SMARCA2 mutant hESCs were phenotypically normal, differentiation to neural progenitors cells (NPCs) was severely impaired. We find that SMARCA2 mutations cause enhancer reorganization with loss of SOX3-dependent neural enhancers and prominent emergence of astrocyte-specific de novo enhancers. Changes in chromatin accessibility at enhancers were associated with an increase in SMARCA2 binding and retargeting of SMARCA4. We show that the AP-1 family member FRA2 is aberrantly overexpressed in SMARCA2 mutant NPCs, where it functions as a pioneer factor at de novo enhancers. Together, our results demonstrate that SMARCA2 mutations cause impaired differentiation through enhancer reprogramming via inappropriate targeting of SMARCA4.
Assuntos
DNA Helicases/metabolismo , Elementos Facilitadores Genéticos , Heterozigoto , Células-Tronco Embrionárias Humanas/metabolismo , Mutação de Sentido Incorreto , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Substituição de Aminoácidos , Diferenciação Celular/genética , Cromatina/genética , Cromatina/metabolismo , DNA Helicases/genética , Fácies , Deformidades Congênitas do Pé/genética , Deformidades Congênitas do Pé/metabolismo , Deformidades Congênitas do Pé/patologia , Antígeno 2 Relacionado a Fos/biossíntese , Antígeno 2 Relacionado a Fos/genética , Células HEK293 , Células-Tronco Embrionárias Humanas/patologia , Humanos , Hipotricose/genética , Hipotricose/metabolismo , Hipotricose/patologia , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Proteínas Nucleares/genética , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Fatores de Transcrição/genéticaRESUMO
De novo variants are a leading cause of neurodevelopmental disorders (NDDs), but because every monogenic NDD is different and usually extremely rare, it remains a major challenge to understand the complete phenotype and genotype spectrum of any morbid gene. According to OMIM, heterozygous variants in KDM6B cause "neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities." Here, by examining the molecular and clinical spectrum of 85 reported individuals with mostly de novo (likely) pathogenic KDM6B variants, we demonstrate that this description is inaccurate and potentially misleading. Cognitive deficits are seen consistently in all individuals, but the overall phenotype is highly variable. Notably, coarse facies and distal skeletal anomalies, as defined by OMIM, are rare in this expanded cohort while other features are unexpectedly common (e.g., hypotonia, psychosis, etc.). Using 3D protein structure analysis and an innovative dual Drosophila gain-of-function assay, we demonstrated a disruptive effect of 11 missense/in-frame indels located in or near the enzymatic JmJC or Zn-containing domain of KDM6B. Consistent with the role of KDM6B in human cognition, we demonstrated a role for the Drosophila KDM6B ortholog in memory and behavior. Taken together, we accurately define the broad clinical spectrum of the KDM6B-related NDD, introduce an innovative functional testing paradigm for the assessment of KDM6B variants, and demonstrate a conserved role for KDM6B in cognition and behavior. Our study demonstrates the critical importance of international collaboration, sharing of clinical data, and rigorous functional analysis of genetic variants to ensure correct disease diagnosis for rare disorders.
Assuntos
Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Humanos , Animais , Fácies , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Fenótipo , Drosophila , Deficiência Intelectual/patologia , Histona Desmetilases com o Domínio Jumonji/genéticaRESUMO
BACKGROUND: Pediatric disorders include a range of highly penetrant, genetically heterogeneous conditions amenable to genomewide diagnostic approaches. Finding a molecular diagnosis is challenging but can have profound lifelong benefits. METHODS: We conducted a large-scale sequencing study involving more than 13,500 families with probands with severe, probably monogenic, difficult-to-diagnose developmental disorders from 24 regional genetics services in the United Kingdom and Ireland. Standardized phenotypic data were collected, and exome sequencing and microarray analyses were performed to investigate novel genetic causes. We developed an iterative variant analysis pipeline and reported candidate variants to clinical teams for validation and diagnostic interpretation to inform communication with families. Multiple regression analyses were performed to evaluate factors affecting the probability of diagnosis. RESULTS: A total of 13,449 probands were included in the analyses. On average, we reported 1.0 candidate variant per parent-offspring trio and 2.5 variants per singleton proband. Using clinical and computational approaches to variant classification, we made a diagnosis in approximately 41% of probands (5502 of 13,449). Of 3599 probands in trios who received a diagnosis by clinical assertion, approximately 76% had a pathogenic de novo variant. Another 22% of probands (2997 of 13,449) had variants of uncertain significance in genes that were strongly linked to monogenic developmental disorders. Recruitment in a parent-offspring trio had the largest effect on the probability of diagnosis (odds ratio, 4.70; 95% confidence interval [CI], 4.16 to 5.31). Probands were less likely to receive a diagnosis if they were born extremely prematurely (i.e., 22 to 27 weeks' gestation; odds ratio, 0.39; 95% CI, 0.22 to 0.68), had in utero exposure to antiepileptic medications (odds ratio, 0.44; 95% CI, 0.29 to 0.67), had mothers with diabetes (odds ratio, 0.52; 95% CI, 0.41 to 0.67), or were of African ancestry (odds ratio, 0.51; 95% CI, 0.31 to 0.78). CONCLUSIONS: Among probands with severe, probably monogenic, difficult-to-diagnose developmental disorders, multimodal analysis of genomewide data had good diagnostic power, even after previous attempts at diagnosis. (Funded by the Health Innovation Challenge Fund and Wellcome Sanger Institute.).
Assuntos
Genômica , Doenças Raras , Criança , Humanos , Exoma , Irlanda/epidemiologia , Reino Unido/epidemiologia , Doenças Raras/diagnóstico , Doenças Raras/epidemiologia , Doenças Raras/genética , Análise de Sequência com Séries de Oligonucleotídeos , Estudos de Associação Genética , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/genética , Anormalidades Congênitas/diagnóstico , Anormalidades Congênitas/genética , Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/genética , Fácies , Transtornos do Comportamento Infantil/diagnóstico , Transtornos do Comportamento Infantil/genética , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genéticaRESUMO
Sensors of the innate immune system that detect intracellular nucleic acids must be regulated to prevent inappropriate activation by endogenous DNA and RNA. The exonuclease Trex1 regulates the DNA-sensing pathway by metabolizing potential DNA ligands that trigger it. However, an analogous mechanism for regulating the RIG-I-like receptors (RLRs) that detect RNA remains unknown. We found here that the SKIV2L RNA exosome potently limited the activation of RLRs. The unfolded protein response (UPR), which generated endogenous RLR ligands through the cleavage of cellular RNA by the endonuclease IRE-1, triggered the production of type I interferons in cells depleted of SKIV2L. Humans with deficiency in SKIV2L had a type I interferon signature in their peripheral blood. Our findings reveal a mechanism for the intracellular metabolism of immunostimulatory RNA, with implications for specific autoimmune disorders.
Assuntos
RNA Helicases DEAD-box/imunologia , Diarreia Infantil/imunologia , Endorribonucleases/imunologia , Complexo Multienzimático de Ribonucleases do Exossomo , Retardo do Crescimento Fetal/imunologia , Doenças do Cabelo/imunologia , Imunidade Inata/imunologia , Proteínas Nucleares/imunologia , Proteínas Serina-Treonina Quinases/imunologia , RNA Helicases/imunologia , Proteínas de Ligação a RNA/imunologia , Resposta a Proteínas não Dobradas/imunologia , Animais , Proteína DEAD-box 58 , Fácies , Técnicas de Silenciamento de Genes , Humanos , Interferon Tipo I/imunologia , Camundongos Endogâmicos C57BL , Proteínas/imunologiaRESUMO
Pathogenic variants in ANKRD11 or microdeletions at 16q24.3 are the cause of KBG syndrome (KBGS), a neurodevelopmental syndrome characterized by intellectual disability, dental and skeletal anomalies, and characteristic facies. The ANKRD11 gene encodes the ankyrin repeat-containing protein 11A transcriptional regulator, which is expressed in the brain and implicated in neural development. Syndromic conditions caused by pathogenic variants in epigenetic regulatory genes show unique patterns of DNA methylation (DNAm) in peripheral blood, termed DNAm signatures. Given ANKRD11's role in chromatin modification, we tested whether pathogenic ANKRD11 variants underlying KBGS are associated with a DNAm signature. We profiled whole-blood DNAm in 21 individuals with ANKRD11 variants, 2 individuals with microdeletions at 16q24.3 and 28 typically developing individuals, using Illumina's Infinium EPIC array. We identified 95 differentially methylated CpG sites that distinguished individuals with KBGS and pathogenic variants in ANKRD11 (n = 14) from typically developing controls (n = 28). This DNAm signature was then validated in an independent cohort of seven individuals with KBGS and pathogenic ANKRD11 variants. We generated a machine learning model from the KBGS DNAm signature and classified the DNAm profiles of four individuals with variants of uncertain significance (VUS) in ANKRD11. We identified an intermediate classification score for an inherited missense variant transmitted from a clinically unaffected mother to her affected child. In conclusion, we show that the DNAm profiles of two individuals with 16q24.3 microdeletions were indistinguishable from the DNAm profiles of individuals with pathogenic variants in ANKRD11, and we demonstrate the diagnostic utility of the new KBGS signature by classifying the DNAm profiles of individuals with VUS in ANKRD11.
Assuntos
Anormalidades Múltiplas , Proteínas Repressoras , Criança , Feminino , Humanos , Anormalidades Múltiplas/sangue , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/sangue , Doenças do Desenvolvimento Ósseo/diagnóstico , Doenças do Desenvolvimento Ósseo/genética , Deleção Cromossômica , Metilação de DNA/genética , Epigênese Genética/genética , Fácies , Deficiência Intelectual/sangue , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Aprendizado de Máquina , Mutação , Fenótipo , Proteínas Repressoras/genética , Anormalidades Dentárias/sangue , Anormalidades Dentárias/diagnóstico , Anormalidades Dentárias/genética , Fatores de Transcrição/genéticaRESUMO
Kinesin motors play a fundamental role in development by controlling intracellular transport, spindle assembly, and microtubule organization. In humans, patients carrying mutations in KIF11 suffer from an autosomal dominant inheritable disease called microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR). While mitotic functions of KIF11 proteins have been well documented in centrosome separation and spindle assembly, cellular mechanisms underlying KIF11 dysfunction and MCLMR remain unclear. In this study, we generate KIF11-inhibition chick and zebrafish models and find that KIF11 inhibition results in microcephaly, chorioretinopathy, and severe developmental defects in vivo. Notably, loss-of-function of KIF11 causes the formation of monopolar spindle and chromosome misalignment, which finally contribute to cell cycle arrest, chromosome instability, and cell death. Our results demonstrate that KIF11 is crucial for spindle assembly, chromosome alignment, and cell cycle progression of progenitor stem cells, indicating a potential link between polyploidy and MCLMR. Our data have revealed that KIF11 inhibition cause microcephaly, chorioretinopathy, and development disorders through the formation of monopolar spindle, polyploid, and cell cycle arrest.
Assuntos
Fácies , Linfedema , Microcefalia , Doenças Retinianas , Displasia Retiniana , Animais , Pontos de Checagem do Ciclo Celular/genética , Instabilidade Cromossômica , Deficiências do Desenvolvimento , Cinesinas/genética , Cinesinas/metabolismo , Microcefalia/genética , Fenótipo , Peixe-Zebra/genética , Peixe-Zebra/metabolismoRESUMO
BACKGROUND: Pathogenic variants in the zinc finger protein coding genes are rare causes of intellectual disability and congenital malformations. Mutations in the ZNF148 gene causing GDACCF syndrome (global developmental delay, absent or hypoplastic corpus callosum, dysmorphic facies; MIM #617260) have been reported in five individuals so far. METHODS: As a result of an international collaboration using GeneMatcher Phenome Central Repository and personal communications, here we describe the clinical and molecular genetic characteristics of 22 previously unreported individuals. RESULTS: The core clinical phenotype is characterised by developmental delay particularly in the domain of speech development, postnatal growth retardation, microcephaly and facial dysmorphism. Corpus callosum abnormalities appear less frequently than suggested by previous observations. The identified mutations concerned nonsense or frameshift variants that were mainly located in the last exon of the ZNF148 gene. Heterozygous deletion including the entire ZNF148 gene was found in only one case. Most mutations occurred de novo, but were inherited from an affected parent in two families. CONCLUSION: The GDACCF syndrome is clinically diverse, and a genotype-first approach, that is, exome sequencing is recommended for establishing a genetic diagnosis rather than a phenotype-first approach. However, the syndrome may be suspected based on some recurrent, recognisable features. Corpus callosum anomalies were not as constant as previously suggested, we therefore recommend to replace the term 'GDACCF syndrome' with 'ZNF148-related neurodevelopmental disorder'.
Assuntos
Deficiência Intelectual , Leucoencefalopatias , Humanos , Criança , Corpo Caloso , Fácies , Mutação/genética , Fenótipo , Genótipo , Deficiência Intelectual/genética , Deficiência Intelectual/diagnóstico , Síndrome , Deficiências do Desenvolvimento/patologia , Proteínas de Ligação a DNA/genética , Fatores de Transcrição/genéticaRESUMO
Schaaf-Yang syndrome (SYS) is an ultra-rare neurodevelopmental disorder caused by truncating mutations in MAGEL2 Heterologous expression of wild-type (WT) or a truncated (p.Gln638*) C-terminal HA-tagged MAGEL2 revealed a shift from a primarily cytoplasmic to a more nuclear localisation for the truncated protein variant. We now extend this analysis to six additional SYS mutations on a N-terminal FLAG-tagged MAGEL2. Our results replicate and extend our previous findings, showing that all the truncated MAGEL2 proteins consistently display a predominant nuclear localisation, irrespective of the C-terminal or N-terminal position and the chemistry of the tag. The variants associated with arthrogryposis multiplex congenita display a more pronounced nuclear retention phenotype, suggesting a correlation between clinical severity and the degree of nuclear mislocalisation. These results point to a neomorphic effect of truncated MAGEL2, which might contribute to the pathogenesis of SYS.
Assuntos
Núcleo Celular , Proteínas de Neoplasias , Humanos , Núcleo Celular/metabolismo , Núcleo Celular/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Mutação , Fenótipo , Artrogripose/genética , Artrogripose/patologia , Citoplasma/metabolismo , Citoplasma/genética , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Transporte Proteico , Células HEK293 , Hipopituitarismo , Fácies , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas Intrinsicamente Desordenadas , Transtornos da Impressão Genômica , Deficiências do Desenvolvimento , Transtornos CromossômicosRESUMO
Pierpont syndrome is a rare disorder characterized mainly by global developmental delay, unusual facial features, altered fat distribution in the limbs and hearing loss. A specific mutation (p.Tyr446Cys) in TBL1XR1, encoding a WD40 repeat-containing protein, which is a component of the SMRT/NCoR (silencing mediator retinoid and thyroid hormone receptors/nuclear receptor corepressors), has been reported as the genetic cause of Pierpont syndrome. Here, we used CRISPR-cas9 technology to generate a mutant mouse with the Y446C mutation in Tbl1xr1, which is also present in Pierpont syndrome. Several aspects of the phenotype were studied in the mutant mice: growth, body composition, hearing, motor behavior, thyroid hormone state and lipid and glucose metabolism. The mutant mice (Tbl1xr1Y446C/Y446C) displayed delayed growth, altered body composition with increased relative lean mass and impaired hearing. Expression of several genes involved in fatty acid metabolism differed in white adipose tissue, but not in liver or muscle of mutant mice compared to wild-type mice (Tbl1xr1+/+). No difference in thyroid hormone plasma concentrations was observed. Tbl1xr1Y446C/Y446C mice can be used as a model for distinct features of Pierpont syndrome, which will enable future studies on the pathogenic mechanisms underlying the various phenotypic characteristics.
Assuntos
Proteínas Nucleares , Proteínas Repressoras , Animais , Deficiências do Desenvolvimento , Modelos Animais de Doenças , Fácies , Lipomatose , Camundongos , Mutação , Proteínas Nucleares/genética , Receptores dos Hormônios Tireóideos/genética , Receptores dos Hormônios Tireóideos/metabolismo , Proteínas Repressoras/genética , Hormônios TireóideosRESUMO
Cornelia de Lange syndrome (CdLS) is a rare multiorgan developmental disorder caused by pathogenic variants in cohesin genes. It is a genetically and clinically heterogeneous dominant (both autosomal and X-linked) rare disease. Increasing experimental evidence indicates that CdLS is caused by a combination of factors, such as gene expression dysregulation, accumulation of cellular damage and cellular aging, which collectively contribute to the CdLS phenotype. The CdLS phenotype overlaps with a number of related diagnoses such as KBG syndrome and Rubinstein-Taybi syndrome both caused by variants in chromatin-associated factors other than cohesin. The molecular basis underlying these overlapping phenotypes is not clearly defined. Here, we found that cells from individuals with CdLS and CdLS-related diagnoses are characterized by global transcription disturbance and share common dysregulated pathways. Intriguingly, c-MYC (subsequently referred to as MYC) is downregulated in all cell lines and represents a convergent hub lying at the center of dysregulated pathways. Subsequent treatment with estradiol restores MYC expression by modulating cohesin occupancy at its promoter region. In addition, MYC activation leads to modification in expression in hundreds of genes, which in turn reduce the oxidative stress level and genome instability. Together, these results show that MYC plays a pivotal role in the etiopathogenesis of CdLS and CdLS-related diagnoses and represents a potential therapeutic target for these conditions.
Assuntos
Anormalidades Múltiplas , Doenças do Desenvolvimento Ósseo , Síndrome de Cornélia de Lange , Deficiência Intelectual , Anormalidades Dentárias , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Síndrome de Cornélia de Lange/genética , Regulação para Baixo/genética , Fácies , Humanos , Mutação , Fenótipo , Proteínas Proto-Oncogênicas c-mycRESUMO
KBG syndrome (KBGS) is characterized by distinctive facial gestalt, short stature and variable clinical findings. With ageing, some features become more recognizable, allowing a differential diagnosis. We aimed to better characterize natural history of KBGS. In the context of a European collaborative study, we collected the largest cohort of KBGS patients (49). A combined array- based Comparative Genomic Hybridization and next generation sequencing (NGS) approach investigated both genomic Copy Number Variants and SNVs. Intellectual disability (ID) (82%) ranged from mild to moderate with severe ID identified in two patients. Epilepsy was present in 26.5%. Short stature was consistent over time, while occipitofrontal circumference (median value: -0.88 SD at birth) normalized over years. Cerebral anomalies, were identified in 56% of patients and thus represented the second most relevant clinical feature reinforcing clinical suspicion in the paediatric age when short stature and vertebral/dental anomalies are vague. Macrodontia, oligodontia and dental agenesis (53%) were almost as frequent as skeletal anomalies, such as brachydactyly, short fifth finger, fifth finger clinodactyly, pectus excavatum/carinatum, delayed bone age. In 28.5% of individuals, prenatal ultrasound anomalies were reported. Except for three splicing variants, leading to a premature termination, variants were almost all frameshift. Our results, broadening the spectrum of KBGS phenotype progression, provide useful tools to facilitate differential diagnosis and improve clinical management. We suggest to consider a wider range of dental anomalies before excluding diagnosis and to perform a careful odontoiatric/ear-nose-throat (ENT) evaluation in order to look for even submucosal palate cleft given the high percentage of palate abnormalities. NGS approaches, following evidence of antenatal ultrasound anomalies, should include ANKRD11.
Assuntos
Anormalidades Múltiplas , Doenças do Desenvolvimento Ósseo , Nanismo , Deficiência Intelectual , Anormalidades Dentárias , Gravidez , Feminino , Humanos , Fácies , Anormalidades Dentárias/genética , Doenças do Desenvolvimento Ósseo/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/diagnóstico , Deficiência Intelectual/genética , Deficiência Intelectual/diagnóstico , Hibridização Genômica Comparativa , Proteínas Repressoras/genética , Fenótipo , Nanismo/genética , População EuropeiaRESUMO
Heterozygous variants in bromodomain and plant homeodomain containing transcription factor (BPTF) cause the neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL) syndrome (MIM#617755) characterized by intellectual disability, speech delay and postnatal microcephaly. BPTF functions within nucleosome and remodeling factor (NURF), a complex comprising sucrose non-fermenting like (SNF2L), an Imitation SWItching (ISWI) chromatin remodeling protein encoded by the SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 1 (SMARCA1) gene. Surprisingly, ablation of Smarca1 resulted in mice with enlarged brains, a direct contrast to the phenotype of NEDDFL patients. To model the NEDDFL syndrome, we generated forebrain-specific Bptf knockout (Bptf conditional Knockout (cKO)) mice. The Bptf cKO mice were born in normal Mendelian ratios, survived to adulthood but were smaller in size with severe cortical hypoplasia. Prolonged progenitor cell cycle length and a high incidence of cell death reduced the neuronal output. Cortical lamination was also disrupted with reduced proportions of deep layer neurons, and neuronal maturation defects that impaired the acquisition of distinct cell fates (e.g. COUP-TF-interacting protein 2 (Ctip2)+ neurons). RNAseq and pathway analysis identified altered expression of fate-determining transcription factors and the biological pathways involved in neural development, apoptotic signaling and amino acid biosynthesis. Dysregulated genes were enriched for MYC Proto-Oncogene, BHLH Transcription Factor (Myc)-binding sites, a known BPTF transcriptional cofactor. We propose the Bptf cKO mouse as a valuable model for further study of the NEDDFL syndrome.
Assuntos
Antígenos Nucleares , Transtornos do Neurodesenvolvimento , Actinas/metabolismo , Aminoácidos/genética , Animais , Antígenos Nucleares/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Cromatina , Montagem e Desmontagem da Cromatina , Fácies , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Transtornos do Neurodesenvolvimento/genética , Nucleossomos , Sacarose , Síndrome , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
ANKRD11 (ankyrin repeat domain 11) is a chromatin regulator and the only gene associated with KBG syndrome, a rare neurodevelopmental disorder. We have previously shown that Ankrd11 regulates murine embryonic cortical neurogenesis. Here, we show a novel olfactory bulb phenotype in a KBG syndrome mouse model and two diagnosed patients. Conditional knockout of Ankrd11 in murine embryonic neural stem cells leads to aberrant postnatal olfactory bulb development and reduced size due to reduction of the olfactory bulb granule cell layer. We further show that the rostral migratory stream has incomplete migration of neuroblasts, reduced cell proliferation as well as aberrant differentiation of neurons. This leads to reduced neuroblasts and neurons in the olfactory bulb granule cell layer. In vitro, Ankrd11-deficient neural stem cells from the postnatal subventricular zone display reduced migration, proliferation, and neurogenesis. Finally, we describe two clinically and molecularly confirmed KBG syndrome patients with anosmia and olfactory bulb and groove hypo-dysgenesis/agenesis. Our report provides evidence that Ankrd11 is a novel regulator of olfactory bulb development and neuroblast migration. Moreover, our study highlights a novel clinical sign of KBG syndrome linked to ANKRD11 perturbations in mice and humans.
Assuntos
Anormalidades Múltiplas , Doenças do Desenvolvimento Ósseo , Deficiência Intelectual , Anormalidades Dentárias , Humanos , Animais , Camundongos , Fácies , Bulbo Olfatório , Modelos Animais de DoençasRESUMO
PURPOSE: KBG syndrome (KBGS) is a rare neurodevelopmental syndrome caused by haploinsufficiency of ANKRD11. The childhood phenotype is extensively reported but limited for adults. Thus, we aimed to delineate the clinical features of KBGS. METHODS: We collected physician-reported data of adults with molecularly confirmed KBGS through an international collaboration. Moreover, we undertook a systematic literature review to determine the scope of previously reported data. RESULTS: The international collaboration identified 36 adults from 31 unrelated families with KBGS. Symptoms included mild/borderline intellectual disability (n = 22); gross and/or fine motor difficulties (n = 15); psychiatric and behavioral comorbidities including aggression, anxiety, reduced attention span, and autistic features (n = 26); nonverbal (n = 3), seizures with various seizure types and treatment responses (n = 10); ophthalmological comorbidities (n = 20). Cognitive regression during adulthood was reported once. Infrequent features included dilatation of the ascending aorta (n = 2) and autoimmune conditions (n = 4). Education, work, and residence varied, and the diversity of professional and personal roles highlighted the range of abilities seen. The literature review identified 154 adults reported across the literature, and we have summarized the features across both data sets. CONCLUSION: Our study sheds light on the long-term neurodevelopmental outcomes, seizures, behavioral and psychiatric features, and education, work, and living arrangements for adults with KBGS.
Assuntos
Deficiência Intelectual , Fenótipo , Humanos , Adulto , Deficiência Intelectual/genética , Deficiência Intelectual/epidemiologia , Masculino , Feminino , Pessoa de Meia-Idade , Adulto Jovem , Haploinsuficiência/genética , Convulsões/genética , Convulsões/epidemiologia , Médicos , Adolescente , Fácies , Anormalidades Múltiplas , Doenças do Desenvolvimento Ósseo , Anormalidades DentáriasRESUMO
ASXL3-related disorder, sometimes referred to as Bainbridge-Ropers syndrome, was first identified as a distinct neurodevelopmental disorder by Bainbridge et al. in 2013. Since then, there have been a number of case series and single case reports published worldwide. A comprehensive review of the literature was carried out. Abstracts were screened, relevant literature was analysed, and descriptions of common phenotypic features were quantified. ASXL3 variants were collated and categorised. Common phenotypic features comprised global developmental delay or intellectual disability (97%), feeding problems (76%), hypotonia (88%) and characteristic facial features (93%). The majority of genetic variants were de novo truncating variants in exon 11 or 12 of the ASXL3 gene. Several gaps in our knowledge of this disorder were identified, namely, underlying pathophysiology and disease mechanism, disease contribution of missense variants, relevance of variant location, prevalence and penetrance data. Clinical information is currently limited by patient numbers and lack of longitudinal data, which this review aims to address.
Assuntos
Anormalidades Múltiplas , Deficiências do Desenvolvimento , Fácies , Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Criança , Humanos , Deficiências do Desenvolvimento/genética , Fatores de Transcrição/genética , Fenótipo , Síndrome , Deficiência Intelectual/genética , Proteínas Repressoras/genéticaRESUMO
Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder characterised by severe intellectual disability (ID), distinctive facial features and autonomic nervous system dysfunction, caused by TCF4 haploinsufficiency. We clinically diagnosed with PTHS a 14 6/12 -year-old female, who had a normal status of TCF4. The pathogenic c.667del (p.Asp223MetfsTer45) variant in SOX11 was identified through whole exome sequencing (WES). SOX11 variants were initially reported to cause Coffin-Siris syndrome (CSS), characterised by growth restriction, moderate ID, coarse face, hypertrichosis and hypoplastic nails. However, recent studies have provided evidence that they give rise to a distinct neurodevelopmental disorder. To date, SOX11 variants are associated with a variable phenotype, which has been described to resemble CSS in some cases, but never PTHS. By reviewing both clinically and genetically 32 out of 82 subjects reported in the literature with SOX11 variants, for whom detailed information are provided, we found that 7/32 (22%) had a clinical presentation overlapping PTHS. Furthermore, we made a confirmation that overall SOX11 abnormalities feature a distinctive disorder characterised by severe ID, high incidence of microcephaly and low frequency of congenital malformations. Purpose of the present report is to enhance the role of clinical genetics in assessing the individual diagnosis after WES results.
Assuntos
Deficiência Intelectual , Feminino , Humanos , Criança , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Fácies , Hiperventilação/diagnóstico , Hiperventilação/genética , Fenótipo , Fator de Transcrição 4/genética , Fatores de Transcrição SOXC/genéticaRESUMO
KBG syndrome is a rare genetic disorder caused by heterozygous pathogenic variants in ANKRD11. Affected individuals have developmental delay, short stature, characteristic facial features, and other dysmorphic findings. To date, a spectrum of unspecific neuroradiological defects has been reported in KBG patients, such as cortical defects, white matter abnormalities, corpus callosum, and cerebellar vermis hypoplasia.Deep clinical and neuroradiological phenotyping and genotype of a patient presenting with mild cognitive and behavioral problems were obtained after written informed consent.We herein describe the first KBG patient presenting with cerebellar heterotopia, a heterogeneous malformation characterized by the presence of clusters of neurons within the white matter of cerebellar hemispheres.This novel association broadens the neuroradiological spectrum of KBG syndrome, and further prompts to investigate the potential functions of ANKRD11 in cerebellar development.
Assuntos
Cerebelo , Humanos , Cerebelo/diagnóstico por imagem , Cerebelo/anormalidades , Cerebelo/patologia , Deficiência Intelectual/genética , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/patologia , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/patologia , Imageamento por Ressonância Magnética , Masculino , Fácies , Doenças Renais Císticas/genética , Doenças Renais Císticas/diagnóstico por imagem , Doenças Renais Císticas/patologia , Feminino , Síndromes Neurocutâneas/diagnóstico por imagem , Síndromes Neurocutâneas/genética , Síndromes Neurocutâneas/patologia , Criança , Coristoma/diagnóstico por imagem , Coristoma/patologia , Doenças do Desenvolvimento Ósseo , Anormalidades DentáriasRESUMO
Pitt Hopkins Syndrome (PTHS) is a rare syndromic form of autism spectrum disorder (ASD) caused by autosomal dominant mutations in the Transcription Factor 4 (TCF4) gene. TCF4 is a basic helix-loop-helix transcription factor that is critical for neurodevelopment and brain function through its binding to cis-regulatory elements of target genes. One potential therapeutic strategy for PTHS is to identify dysregulated target genes and normalize their dysfunction. Here, we propose that SCN10A is an important target gene of TCF4 that is an applicable therapeutic approach for PTHS. Scn10a encodes the voltage-gated sodium channel Nav1.8 and is consistently shown to be upregulated in PTHS mouse models. In this perspective, we review prior literature and present novel data that suggests inhibiting Nav1.8 in PTHS mouse models is effective at normalizing neuron function, brain circuit activity and behavioral abnormalities and posit this therapeutic approach as a treatment for PTHS.
Assuntos
Deficiência Intelectual , Canal de Sódio Disparado por Voltagem NAV1.8 , Animais , Camundongos , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/metabolismo , Fácies , Hiperventilação/genética , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Fator de Transcrição 4/genética , Canal de Sódio Disparado por Voltagem NAV1.8/química , Canal de Sódio Disparado por Voltagem NAV1.8/metabolismoRESUMO
Trichohepatoenteric syndrome (THES) is a rare autosomal recessive disorder caused by mutations in either TTC37 or SKIV2L, usually leading to congenital diarrhea as part of a multisystem disease. Here, we report on the natural history of the disease for the largest UK cohort of patients with THES from 1996 to 2020. We systematically reviewed the clinical records and pathological specimens of patients diagnosed with THES managed in a single tertiary pediatric gastroenterology unit. Between 1996 and 2020, 13 patients (7 female and 6 male) were diagnosed with THES either by mutation analysis or by clinical phenotype. Two patients died from complications of infection. All patients received parenteral nutrition (PN) of which six patients were weaned off PN. All patients had gastrointestinal tract inflammation on endoscopy. Almost half of the cohort were diagnosed with monogenic inflammatory bowel disease (IBD) by the age of 11 years, confirmed by endoscopic and histological findings. Protracted diarrhea causing intestinal failure improves with time in all patients with THES, but monogenic IBD develops in later childhood that is refractory to conventional IBD treatments. Respiratory issues contribute to significant morbidity and mortality, and good respiratory care is crucial to prevent comorbidity.