RESUMO
Eukaryotic initiation factor-4A2 (EIF4A2) is an ATP-dependent RNA helicase and a member of the DEAD-box protein family that recognizes the 5' cap structure of mRNAs, allows mRNA to bind to the ribosome, and plays an important role in microRNA-regulated gene repression. Here, we report on 15 individuals from 14 families presenting with global developmental delay, intellectual disability, hypotonia, epilepsy, and structural brain anomalies, all of whom have extremely rare de novo mono-allelic or inherited bi-allelic variants in EIF4A2. Neurodegeneration was predominantly reported in individuals with bi-allelic variants. Molecular modeling predicts these variants would perturb structural interactions in key protein domains. To determine the pathogenicity of the EIF4A2 variants in vivo, we examined the mono-allelic variants in Drosophila melanogaster (fruit fly) and identified variant-specific behavioral and developmental defects. The fruit fly homolog of EIF4A2 is eIF4A, a negative regulator of decapentaplegic (dpp) signaling that regulates embryo patterning, eye and wing morphogenesis, and stem cell identity determination. Our loss-of-function (LOF) rescue assay demonstrated a pupal lethality phenotype induced by loss of eIF4A, which was fully rescued with human EIF4A2 wild-type (WT) cDNA expression. In comparison, the EIF4A2 variant cDNAs failed or incompletely rescued the lethality. Overall, our findings reveal that EIF4A2 variants cause a genetic neurodevelopmental syndrome with both LOF and gain of function as underlying mechanisms.
Assuntos
Proteínas de Drosophila , Epilepsia , Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Animais , Humanos , Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Proteínas de Drosophila/genética , Epilepsia/genética , Fator de Iniciação 4A em Eucariotos/genética , Deficiência Intelectual/genética , Hipotonia Muscular/genética , Transtornos do Neurodesenvolvimento/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
Inosine 5' monophosphate dehydrogenase (IMPDH) is a critical regulatory enzyme in purine nucleotide biosynthesis that is inhibited by the downstream product GTP. Multiple point mutations in the human isoform IMPDH2 have recently been associated with dystonia and other neurodevelopmental disorders, but the effect of the mutations on enzyme function has not been described. Here, we report the identification of two additional missense variants in IMPDH2 from affected individuals and show that all of the disease-associated mutations disrupt GTP regulation. Cryo-EM structures of one IMPDH2 mutant suggest this regulatory defect arises from a shift in the conformational equilibrium toward a more active state. This structural and functional analysis provides insight into IMPDH2-associated disease mechanisms that point to potential therapeutic approaches and raises new questions about fundamental aspects of IMPDH regulation.
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IMP Desidrogenase , Purinas , Humanos , Regulação Alostérica , IMP Desidrogenase/genética , IMP Desidrogenase/metabolismo , Mutação , Guanosina TrifosfatoRESUMO
General transcription factor IIIC subunit 5 (GTF3C5) encodes transcription factor IIIC63 (TFIIIC63). It binds to DNA to recruit another transcription factor, TFIIIB, and RNA polymerase III (Pol III) to mediate the transcription of small noncoding RNAs, such as tRNAs. Here, we report four individuals from three families presenting with a multisystem developmental disorder phenotype with biallelic variants in GTF3C5. The overlapping features include growth retardation, developmental delay, intellectual disability, dental anomalies, cerebellar malformations, delayed bone age, skeletal anomalies, and facial dysmorphism. Using lymphoblastoid cell lines (LCLs) from two affected individuals, we observed a reduction in TFIIIC63 protein levels compared to control LCLs. Genome binding of TFIIIC63 protein is also reduced in LCL from one of the affected individuals. Additionally, approximately 40% of Pol III binding regions exhibited reduction in the level of Pol III occupancy in the mutant genome relative to the control, while approximately 54% of target regions showed comparable levels of Pol III occupancy between the two, indicating partial impairment of Pol III occupancy in the mutant genome. Yeasts with subject-specific variants showed temperature sensitivity and impaired growth, supporting the notion that the identified variants have deleterious effects. gtf3c5 mutant zebrafish showed developmental defects, including a smaller body, head, and eyes. Taken together, our data show that GTF3C5 plays an important role in embryonic development, and that biallelic variants in this gene cause a multisystem developmental disorder. Our study adds GTF3C5-related disorder to the growing list of genetic disorders associated with Pol III transcription machinery.
Assuntos
Deficiências do Desenvolvimento , RNA Polimerase III , Fatores de Transcrição TFIII , Animais , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Alelos , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Deficiência Intelectual/genética , Mutação , Linhagem , Fenótipo , RNA Polimerase III/genética , RNA Polimerase III/metabolismo , Fatores de Transcrição TFII/genética , Fatores de Transcrição TFII/metabolismo , Fatores de Transcrição TFIII/genética , Fatores de Transcrição TFIII/metabolismo , Transcrição Gênica , Peixe-Zebra/genéticaRESUMO
EDEM3 encodes a protein that converts Man8GlcNAc2 isomer B to Man7-5GlcNAc2. It is involved in the endoplasmic reticulum-associated degradation pathway, responsible for the recognition of misfolded proteins that will be targeted and translocated to the cytosol and degraded by the proteasome. In this study, through a combination of exome sequencing and gene matching, we have identified seven independent families with 11 individuals with bi-allelic protein-truncating variants and one individual with a compound heterozygous missense variant in EDEM3. The affected individuals present with an inherited congenital disorder of glycosylation (CDG) consisting of neurodevelopmental delay and variable facial dysmorphisms. Experiments in human fibroblast cell lines, human plasma, and mouse plasma and brain tissue demonstrated decreased trimming of Man8GlcNAc2 isomer B to Man7GlcNAc2, consistent with loss of EDEM3 enzymatic activity. In human cells, Man5GlcNAc2 to Man4GlcNAc2 conversion is also diminished with an increase of Glc1Man5GlcNAc2. Furthermore, analysis of the unfolded protein response showed a reduced increase in EIF2AK3 (PERK) expression upon stimulation with tunicamycin as compared to controls, suggesting an impaired unfolded protein response. The aberrant plasma N-glycan profile provides a quick, clinically available test for validating variants of uncertain significance that may be identified by molecular genetic testing. We propose to call this deficiency EDEM3-CDG.
Assuntos
Proteínas de Ligação ao Cálcio/genética , Defeitos Congênitos da Glicosilação/genética , Retículo Endoplasmático/genética , alfa-Manosidase/genética , Adolescente , Alelos , Proteínas de Ligação ao Cálcio/deficiência , Linhagem Celular , Criança , Pré-Escolar , Defeitos Congênitos da Glicosilação/sangue , Deficiências do Desenvolvimento/genética , Feminino , Glicoproteínas/sangue , Glicosilação , Humanos , Lactente , Deficiência Intelectual/genética , Masculino , Mutação , Linhagem , Polissacarídeos/sangue , Deficiências na Proteostase/genética , alfa-Manosidase/deficiênciaRESUMO
OBJECTIVE: To assess the diagnostic yield of exome sequencing (ES) in pediatric cardiomyopathy. STUDY DESIGN: A single-institution, retrospective chart review of 91 patients with pediatric cardiomyopathy was performed. While pediatric cardiomyopathy is often genetic in nature, no genetic test is recommended as standard of care. All our patients were diagnosed with cardiomyopathy and evaluated by a medical geneticist between January 2010 through September 2022. Demographic information and clinical data were abstracted. RESULTS: Of 91 patients with pediatric cardiomyopathy, 36 (39.6%) received a diagnosis by ES. Twenty-two (61.1%) of these diagnoses would have been missed on cardiac multigene panel testing. The diagnostic yield for cardiomyopathy presenting under 1 year of age was 38.3%, while the yield for patients over 1 year of age was 41.9%. CONCLUSIONS: ES has a high diagnostic yield in pediatric cardiomyopathy compared with a gene panel. Over 60% of patients with diagnosis by ES would not have received their molecular genetic diagnosis if only multigene panel testing was sent. Diagnostic yield did not vary significantly between the subtypes of cardiomyopathy and patient age groups, highlighting the likely clinical utility of ES for all pediatric cardiomyopathy patients.
Assuntos
Cardiomiopatias , Médicos , Humanos , Criança , Sequenciamento do Exoma , Estudos Retrospectivos , Testes Genéticos , Cardiomiopatias/diagnóstico , Cardiomiopatias/genéticaRESUMO
Kabuki syndrome is a recognizable Mendelian disorder characterized by the clinical constellation of childhood hypotonia, developmental delay or intellectual impairment, and characteristic dysmorphism resulting from monoallelic pathogenic variants in KMT2D or KDM6A. In the medical literature, most reported patients are children, and data is lacking on the natural history of the condition across the lifespan, with little known about adult-specific presentations and symptoms. Here, we report the results of a retrospective chart review of eight adult patients with Kabuki syndrome, seven of whom are molecularly confirmed. We use their trajectories to highlight the diagnostic challenges unique to an adult population, expand on neurodevelopmental/psychiatric phenotypes across the lifespan, and describe adult-onset medical complications, including a potential cancer risk and unusual and striking premature/accelerated aging phenotype.
Assuntos
Anormalidades Múltiplas , Doenças Hematológicas , Humanos , Estudos Retrospectivos , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Face/patologia , Doenças Hematológicas/diagnóstico , Doenças Hematológicas/genética , Doenças Hematológicas/complicações , Fenótipo , MutaçãoRESUMO
Nuclear speckles are small, membrane-less organelles that reside within the nucleus. Nuclear speckles serve as a regulatory hub coordinating complex RNA metabolism steps including gene transcription, pre-mRNA splicing, RNA modifications, and mRNA nuclear export. Reflecting the importance of proper nuclear speckle function in regulating normal human development, an increasing number of genetic disorders have been found to result from mutations in the genes encoding nuclear speckle proteins. To denote this growing class of genetic disorders, we propose "nuclear speckleopathies". Notably, developmental disabilities are commonly seen in individuals with nuclear speckleopathies, suggesting the particular importance of nuclear speckles in ensuring normal neurocognitive development. In this review article, a general overview of nuclear speckle function, and the current knowledge of the mechanisms underlying some nuclear speckleopathies, such as ZTTK syndrome, NKAP-related syndrome, TARP syndrome, and TAR syndrome, are discussed. These nuclear speckleopathies represent valuable models to understand the basic function of nuclear speckles and how its functional defects result in human developmental disorders.
RESUMO
PURPOSE: This study aimed to establish variants in CBX1, encoding heterochromatin protein 1ß (HP1ß), as a cause of a novel syndromic neurodevelopmental disorder. METHODS: Patients with CBX1 variants were identified, and clinician researchers were connected using GeneMatcher and physician referrals. Clinical histories were collected from each patient. To investigate the pathogenicity of identified variants, we performed in vitro cellular assays and neurobehavioral and cytological analyses of neuronal cells obtained from newly generated Cbx1 mutant mouse lines. RESULTS: In 3 unrelated individuals with developmental delay, hypotonia, and autistic features, we identified heterozygous de novo variants in CBX1. The identified variants were in the chromodomain, the functional domain of HP1ß, which mediates interactions with chromatin. Cbx1 chromodomain mutant mice displayed increased latency-to-peak response, suggesting the possibility of synaptic delay or myelination deficits. Cytological and chromatin immunoprecipitation experiments confirmed the reduction of mutant HP1ß binding to heterochromatin, whereas HP1ß interactome analysis demonstrated that the majority of HP1ß-interacting proteins remained unchanged between the wild-type and mutant HP1ß. CONCLUSION: These collective findings confirm the role of CBX1 in developmental disabilities through the disruption of HP1ß chromatin binding during neurocognitive development. Because HP1ß forms homodimers and heterodimers, mutant HP1ß likely sequesters wild-type HP1ß and other HP1 proteins, exerting dominant-negative effects.
Assuntos
Homólogo 5 da Proteína Cromobox , Heterocromatina , Animais , Camundongos , Cromatina/genética , Proteínas Cromossômicas não Histona/genética , Histonas/genética , Histonas/metabolismoRESUMO
Eukaryotic translation elongation factor 2 (eEF2), encoded by the gene EEF2, is an essential factor involved in the elongation phase of protein translation. A specific heterozygous missense variant (p.P596H) in EEF2 was originally identified in association with autosomal dominant adult-onset spinocerebellar ataxia-26 (SCA26). More recently, additional heterozygous missense variants in this gene have been described to cause a novel, childhood-onset neurodevelopmental disorder with benign external hydrocephalus. Herein, we report two unrelated individuals with a similar gene-disease correlation to support this latter observation. Patient 1 is a 7-year-old male with a previously reported, de novo missense variant (p.V28M) who has motor and speech delay, autism spectrum disorder, failure to thrive with relative macrocephaly, unilateral microphthalmia with coloboma and eczema. Patient 2 is a 4-year-old female with a novel de novo nonsense variant (p.Q145X) with motor and speech delay, hypotonia, macrocephaly with benign ventricular enlargement, and keratosis pilaris. These additional cases help to further expand the genotypic and phenotypic spectrum of this newly described EEF2-related neurodevelopmental syndrome.
Assuntos
Transtorno do Espectro Autista , Deficiência Intelectual , Transtornos do Desenvolvimento da Linguagem , Transtornos do Neurodesenvolvimento , Masculino , Adulto , Feminino , Humanos , Criança , Pré-Escolar , Transtorno do Espectro Autista/genética , Fator 2 de Elongação de Peptídeos/genética , Transtornos do Neurodesenvolvimento/genética , Transtornos do Desenvolvimento da Linguagem/genética , Genótipo , Deficiência Intelectual/genética , FenótipoRESUMO
SRRM2-related neurodevelopmental disorder is a recently described genetic diagnosis caused by loss-of-function variants in SRRM2. In order to understand the clinical spectrum of SRRM2-related neurodevelopmental disorder, we performed a retrospective exome data and clinical chart review at a single tertiary children's hospital, Children's Hospital of Philadelphia (CHOP). Among approximately 3100 clinical exome sequencing cases performed at CHOP, we identified three patients with SRRM2 loss-of-function pathogenic variants, in addition to one patient previously described in the literature. Common clinical features include developmental delay, attention deficit hyperactivity disorder, macrocephaly, hypotonia, gastroesophageal reflux, overweight/obesity, and autism. While developmental disabilities are commonly seen in all individuals with SRRM2 variants, the degree of developmental delay and intellectual disability is variable. Our data suggest that SRRM2-related neurodevelopmental disorder can be identified in 0.3% of individuals with developmental disabilities receiving exome sequencing.
Assuntos
Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Humanos , Criança , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Estudos Retrospectivos , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Hospitais , Proteínas de Ligação a RNARESUMO
CHD7 disorder is a multiple congenital anomaly syndrome with a highly variable phenotypic spectrum, and includes CHARGE syndrome. Internal and external genital phenotypes frequently seen in CHD7 disorder include cryptorchidism and micropenis in males, and vaginal hypoplasia in females, both thought to be secondary to hypogonadotropic hypogonadism. Here, we report 14 deeply phenotyped individuals with known CHD7 variants (9 pathogenic/likely pathogenic and 5 VOUS) and a range of reproductive and endocrine phenotypes. Reproductive organ anomalies were observed in 8 of 14 individuals and were more commonly noted in males (7/7), most of whom presented with micropenis and/or cryptorchidism. Kallmann syndrome was commonly observed among adolescents and adults with CHD7 variants. Remarkably, one 46,XY individual presented with ambiguous genitalia, cryptorchidism with Müllerian structures including uterus, vagina and fallopian tubes, and one 46,XX female patient presented with absent vagina, uterus and ovaries. These cases expand the genital and reproductive phenotype of CHD7 disorder to include two individuals with genital/gonadal atypia (ambiguous genitalia), and one with Müllerian aplasia.
Assuntos
Síndrome CHARGE , Criptorquidismo , Transtornos do Desenvolvimento Sexual , Humanos , Masculino , Feminino , Fenótipo , Síndrome CHARGE/genética , Transtornos do Desenvolvimento Sexual/genética , Genitália , DNA Helicases/genética , Proteínas de Ligação a DNA/genéticaRESUMO
De novo variants in QRICH1 (Glutamine-rich protein 1) has recently been reported in 11 individuals with intellectual disability (ID). The function of QRICH1 is largely unknown but it is likely to play a key role in the unfolded response of endoplasmic reticulum stress through transcriptional control of proteostasis. In this study, we present 27 additional individuals and delineate the clinical and molecular spectrum of the individuals (n = 38) with QRICH1 variants. The main clinical features were mild to moderate developmental delay/ID (71%), nonspecific facial dysmorphism (92%) and hypotonia (39%). Additional findings included poor weight gain (29%), short stature (29%), autism spectrum disorder (29%), seizures (24%) and scoliosis (18%). Minor structural brain abnormalities were reported in 52% of the individuals with brain imaging. Truncating or splice variants were found in 28 individuals and 10 had missense variants. Four variants were inherited from mildly affected parents. This study confirms that heterozygous QRICH1 variants cause a neurodevelopmental disorder including short stature and expands the phenotypic spectrum to include poor weight gain, scoliosis, hypotonia, minor structural brain anomalies, and seizures. Inherited variants from mildly affected parents are reported for the first time, suggesting variable expressivity.
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Transtorno do Espectro Autista , Nanismo , Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Escoliose , Transtorno do Espectro Autista/genética , Humanos , Deficiência Intelectual/genética , Hipotonia Muscular , Transtornos do Neurodesenvolvimento/genética , Convulsões , Aumento de PesoRESUMO
Mutations in several genes encoding components of the SWI/SNF chromatin remodeling complex cause neurodevelopmental disorders (NDDs). Here, we report on five individuals with mutations in SMARCD1; the individuals present with developmental delay, intellectual disability, hypotonia, feeding difficulties, and small hands and feet. Trio exome sequencing proved the mutations to be de novo in four of the five individuals. Mutations in other SWI/SNF components cause Coffin-Siris syndrome, Nicolaides-Baraitser syndrome, or other syndromic and non-syndromic NDDs. Although the individuals presented here have dysmorphisms and some clinical overlap with these syndromes, they lack their typical facial dysmorphisms. To gain insight into the function of SMARCD1 in neurons, we investigated the Drosophila ortholog Bap60 in postmitotic memory-forming neurons of the adult Drosophila mushroom body (MB). Targeted knockdown of Bap60 in the MB of adult flies causes defects in long-term memory. Mushroom-body-specific transcriptome analysis revealed that Bap60 is required for context-dependent expression of genes involved in neuron function and development in juvenile flies when synaptic connections are actively being formed in response to experience. Taken together, we identify an NDD caused by SMARCD1 mutations and establish a role for the SMARCD1 ortholog Bap60 in the regulation of neurodevelopmental genes during a critical time window of juvenile adult brain development when neuronal circuits that are required for learning and memory are formed.
Assuntos
Proteínas Cromossômicas não Histona/genética , Memória , Transtornos do Neurodesenvolvimento/genética , Neurônios/metabolismo , Animais , Criança , Pré-Escolar , Deficiências do Desenvolvimento/genética , Modelos Animais de Doenças , Proteínas de Drosophila/genética , Drosophila melanogaster , Feminino , Regulação da Expressão Gênica , Humanos , Deficiência Intelectual/genética , Aprendizagem , Masculino , Mitose , Hipotonia Muscular/genética , Corpos Pedunculados , Mutação , Síndrome , Fatores de Transcrição/genéticaRESUMO
POU3F3, also referred to as Brain-1, is a well-known transcription factor involved in the development of the central nervous system, but it has not previously been associated with a neurodevelopmental disorder. Here, we report the identification of 19 individuals with heterozygous POU3F3 disruptions, most of which are de novo variants. All individuals had developmental delays and/or intellectual disability and impairments in speech and language skills. Thirteen individuals had characteristic low-set, prominent, and/or cupped ears. Brain abnormalities were observed in seven of eleven MRI reports. POU3F3 is an intronless gene, insensitive to nonsense-mediated decay, and 13 individuals carried protein-truncating variants. All truncating variants that we tested in cellular models led to aberrant subcellular localization of the encoded protein. Luciferase assays demonstrated negative effects of these alleles on transcriptional activation of a reporter with a FOXP2-derived binding motif. In addition to the loss-of-function variants, five individuals had missense variants that clustered at specific positions within the functional domains, and one small in-frame deletion was identified. Two missense variants showed reduced transactivation capacity in our assays, whereas one variant displayed gain-of-function effects, suggesting a distinct pathophysiological mechanism. In bioluminescence resonance energy transfer (BRET) interaction assays, all the truncated POU3F3 versions that we tested had significantly impaired dimerization capacities, whereas all missense variants showed unaffected dimerization with wild-type POU3F3. Taken together, our identification and functional cell-based analyses of pathogenic variants in POU3F3, coupled with a clinical characterization, implicate disruptions of this gene in a characteristic neurodevelopmental disorder.
Assuntos
Regulação da Expressão Gênica , Mutação , Transtornos do Neurodesenvolvimento/etiologia , Fatores do Domínio POU/genética , Ativação Transcricional , Sequência de Aminoácidos , Criança , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Transtornos do Neurodesenvolvimento/patologia , Fatores do Domínio POU/química , Conformação Proteica , Homologia de SequênciaRESUMO
NKAP is a ubiquitously expressed nucleoplasmic protein that is currently known as a transcriptional regulatory molecule via its interaction with HDAC3 and spliceosomal proteins. Here, we report a disorder of transcriptional regulation due to missense mutations in the X chromosome gene, NKAP. These mutations are clustered in the C-terminal region of NKAP where NKAP interacts with HDAC3 and post-catalytic spliceosomal complex proteins. Consistent with a role for the C-terminal region of NKAP in embryogenesis, nkap mutant zebrafish with a C-terminally truncated NKAP demonstrate severe developmental defects. The clinical features of affected individuals are highly conserved and include developmental delay, hypotonia, joint contractures, behavioral abnormalities, Marfanoid habitus, and scoliosis. In affected cases, transcriptome analysis revealed the presence of a unique transcriptome signature, which is characterized by the downregulation of long genes with higher exon numbers. These observations indicate the critical role of NKAP in transcriptional regulation and demonstrate that perturbations of the C-terminal region lead to developmental defects in both humans and zebrafish.
Assuntos
Disfunção Cognitiva/genética , Mutação de Sentido Incorreto/genética , Proteínas Repressoras/genética , Transcrição Gênica/genética , Sequência de Aminoácidos , Animais , Regulação para Baixo/genética , Éxons/genética , Regulação da Expressão Gênica/genética , Genes Ligados ao Cromossomo X/genética , Histona Desacetilases/genética , Humanos , Alinhamento de Sequência , Transcriptoma/genética , Peixe-Zebra/genéticaRESUMO
PURPOSE: This study aimed to describe the phenotypic and molecular characteristics of ARCN1-related syndrome. METHODS: Patients with ARCN1 variants were identified, and clinician researchers were connected using GeneMatcher and physician referrals. Clinical histories were collected from each patient. RESULTS: In total, we identified 14 cases of ARCN1-related syndrome, (9 pediatrics, and 5 fetal cases from 3 families). The clinical features these newly identified cases were compared to 6 previously reported cases for a total of 20 cases. Intrauterine growth restriction, micrognathia, and short stature were present in all patients. Other common features included prematurity (11/15, 73.3%), developmental delay (10/14, 71.4%), genitourinary malformations in males (6/8, 75%), and microcephaly (12/15, 80%). Novel features of ARCN1-related syndrome included transient liver dysfunction and specific glycosylation abnormalities during illness, giant cell hepatitis, hepatoblastoma, cataracts, and lethal skeletal manifestations. Developmental delay was seen in 73% of patients, but only 3 patients had intellectual disability, which is less common than previously reported. CONCLUSION: ARCN1-related syndrome presents with a wide clinical spectrum ranging from a severe embryonic lethal syndrome to a mild syndrome with intrauterine growth restriction, micrognathia, and short stature without intellectual disability. Patients with ARCN1-related syndrome should be monitored for liver dysfunction during illness, cataracts, and hepatoblastoma. Additional research to further define the phenotypic spectrum and possible genotype-phenotype correlations are required.
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Catarata , Nanismo , Hepatoblastoma , Deficiência Intelectual , Neoplasias Hepáticas , Micrognatismo , Criança , Feminino , Retardo do Crescimento Fetal/genética , Humanos , Deficiência Intelectual/genética , Masculino , Fenótipo , SíndromeRESUMO
PURPOSE: SRRM2 encodes the SRm300 protein, a splicing factor of the SR-related protein family characterized by its serine- and arginine-enriched domains. It promotes interactions between messenger RNA and the spliceosome catalytic machinery. This gene, predicted to be highly intolerant to loss of function (LoF) and very conserved through evolution, has not been previously reported in constitutive human disease. METHODS: Among the 1000 probands studied with developmental delay and intellectual disability in our database, we found 2 patients with de novo LoF variants in SRRM2. Additional families were identified through GeneMatcher. RESULTS: Here, we report on 22 patients with LoF variants in SRRM2 and provide a description of the phenotype. Molecular analysis identified 12 frameshift variants, 8 nonsense variants, and 2 microdeletions of 66 kb and 270 kb. The patients presented with a mild developmental delay, predominant speech delay, autistic or attention-deficit/hyperactivity disorder features, overfriendliness, generalized hypotonia, overweight, and dysmorphic facial features. Intellectual disability was variable and mild when present. CONCLUSION: We established SRRM2 as a gene responsible for a rare neurodevelopmental disease.
Assuntos
Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Proteínas de Ligação a RNA/genética , Criança , Deficiências do Desenvolvimento/genética , Humanos , Deficiência Intelectual/genética , Hipotonia Muscular/genética , Transtornos do Neurodesenvolvimento/genética , FenótipoRESUMO
PURPOSE: Germline loss-of-function variants in CTNNB1 cause neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; OMIM 615075) and are the most frequent, recurrent monogenic cause of cerebral palsy (CP). We investigated the range of clinical phenotypes owing to disruptions of CTNNB1 to determine the association between NEDSDV and CP. METHODS: Genetic information from 404 individuals with collectively 392 pathogenic CTNNB1 variants were ascertained for the study. From these, detailed phenotypes for 52 previously unpublished individuals were collected and combined with 68 previously published individuals with comparable clinical information. The functional effects of selected CTNNB1 missense variants were assessed using TOPFlash assay. RESULTS: The phenotypes associated with pathogenic CTNNB1 variants were similar. A diagnosis of CP was not significantly associated with any set of traits that defined a specific phenotypic subgroup, indicating that CP is not additional to NEDSDV. Two CTNNB1 missense variants were dominant negative regulators of WNT signaling, highlighting the utility of the TOPFlash assay to functionally assess variants. CONCLUSION: NEDSDV is a clinically homogeneous disorder irrespective of initial clinical diagnoses, including CP, or entry points for genetic testing.
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Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Humanos , Fenótipo , Transtornos do Neurodesenvolvimento/genética , Via de Sinalização Wnt/genética , Deficiência Intelectual/genética , Genômica , beta Catenina/genéticaRESUMO
Liver transplantation (LT) has been used for many years as a therapeutic option for certain inborn errors of metabolism (IEMs). Here we present one institution's 27 years of experience with LT in IEMs. Our objective is to assess the outcomes of IEM patients who have undergone LT, which we hypothesize to be generally successful for prevention of metabolic decompensation. A retrospective chart review was performed on patients with urea cycle defects, organic acidemias, and amino acidopathies who underwent LT at the Children's Hospital of Philadelphia. Thirty-five patients with the following conditions have undergone LT: tyrosinemia (8), methylmalonic acidemia (7), maple syrup urine disease (6), citrullinemia (6), ornithine transcarbamylase deficiency (4), propionic acidemia (2), and argininosuccinate lyase deficiency (2). Average age at transplantation was 3.6 years. Three patients are now deceased. One patient suffered a metabolic stroke posttransplant. No episodes of metabolic decompensation have been noted. Thirty-five patients received LT with generally favorable outcome. None sustained metabolic decompensation posttransplant. As has been reported previously, LT does not ameliorate pre-existing developmental differences or risk to other organ systems. Further research is needed to aid in standardization of care and follow-up, as most patients no longer follow with a geneticist.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos , Transplante de Fígado , Doença da Urina de Xarope de Bordo , Acidemia Propiônica , Erros Inatos do Metabolismo dos Aminoácidos/terapia , Criança , Hospitais , Humanos , Transplante de Fígado/efeitos adversos , Doença da Urina de Xarope de Bordo/terapia , Acidemia Propiônica/cirurgia , Estudos RetrospectivosRESUMO
MYH7, encoding the myosin heavy chain sarcomeric ß-myosin heavy chain, is a common cause of both hypertrophic and dilated cardiomyopathy. Additionally, families with left ventricular noncompaction cardiomyopathy (LVNC) and congenital heart disease (CHD), typically septal defects or Ebstein anomaly, have been identified to have heterozygous pathogenic variants in MHY7. One previous case of single ventricle CHD with heart failure due to a MYH7 variant has been identified. Herein, we present a single center's experience of complex CHD due to MYH7 variants. Three probands with a history of CHD, LVNC, and/or arrhythmias were identified to have MYH7 variants through multigene panel testing or exome sequencing. These three patients collectively had 12 affected family members, four with a history of Ebstein anomaly and seven with a history of LVNC. These findings suggest a wider phenotypic spectrum in MYH7-related CHD than previously understood. Further investigation into the possible role of MYH7 in CHD and mechanism of disease is necessary to fully delineate the phenotypic spectrum of MYH7-related cardiac disease. MYH7 should be considered for families with multiple individuals with complex CHD in the setting of a family history of LVNC or arrhythmias.