RESUMO
Non-centrosomal microtubules are essential cytoskeletal filaments that are important for neurite formation, axonal transport, and neuronal migration. They require stabilization by microtubule minus-end-targeting proteins including the CAMSAP family of molecules. Using exome sequencing on samples from five unrelated families, we show that bi-allelic CAMSAP1 loss-of-function variants cause a clinically recognizable, syndromic neuronal migration disorder. The cardinal clinical features of the syndrome include a characteristic craniofacial appearance, primary microcephaly, severe neurodevelopmental delay, cortical visual impairment, and seizures. The neuroradiological phenotype comprises a highly recognizable combination of classic lissencephaly with a posterior more severe than anterior gradient similar to PAFAH1B1(LIS1)-related lissencephaly and severe hypoplasia or absence of the corpus callosum; dysplasia of the basal ganglia, hippocampus, and midbrain; and cerebellar hypodysplasia, similar to the tubulinopathies, a group of monogenic tubulin-associated disorders of cortical dysgenesis. Neural cell rosette lineages derived from affected individuals displayed findings consistent with these phenotypes, including abnormal morphology, decreased cell proliferation, and neuronal differentiation. Camsap1-null mice displayed increased perinatal mortality, and RNAScope studies identified high expression levels in the brain throughout neurogenesis and in facial structures, consistent with the mouse and human neurodevelopmental and craniofacial phenotypes. Together our findings confirm a fundamental role of CAMSAP1 in neuronal migration and brain development and define bi-allelic variants as a cause of a clinically distinct neurodevelopmental disorder in humans and mice.
Assuntos
Lissencefalias Clássicas e Heterotopias Subcorticais em Banda , Lisencefalia , Malformações do Sistema Nervoso , Humanos , Animais , Camundongos , Lisencefalia/genética , Alelos , Tubulina (Proteína)/genética , Fenótipo , Malformações do Sistema Nervoso/genética , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/genética , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/genéticaRESUMO
Spermatogenesis-associated 5 like 1 (SPATA5L1) represents an orphan gene encoding a protein of unknown function. We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families. In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy. Modeling indicated damaging effect of variants on the protein, largely via destabilizing effects on protein domains. Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals. Immunofluorescent imaging in rat hippocampal neurons revealed localization of Spata5l1 in neuronal and glial cell nuclei and more prominent expression in neurons. In the rodent inner ear, Spata5l1 is expressed in the neurosensory hair cells and inner ear supporting cells. Transcriptomic analysis performed with fibroblasts from affected individuals was able to distinguish affected from controls by principal components. Analysis of differentially expressed genes and networks suggested a role for SPATA5L1 in cell surface adhesion receptor function, intracellular focal adhesions, and DNA replication and mitosis. Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype.
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Paralisia Cerebral/patologia , Epilepsia/patologia , Predisposição Genética para Doença , Variação Genética , Perda Auditiva/patologia , Deficiência Intelectual/patologia , Espasticidade Muscular/patologia , ATPases Associadas a Diversas Atividades Celulares/genética , Adolescente , Adulto , Alelos , Animais , Paralisia Cerebral/etiologia , Paralisia Cerebral/metabolismo , Pré-Escolar , Epilepsia/etiologia , Epilepsia/metabolismo , Feminino , Perda Auditiva/etiologia , Perda Auditiva/metabolismo , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/etiologia , Deficiência Intelectual/metabolismo , Masculino , Espasticidade Muscular/etiologia , Espasticidade Muscular/metabolismo , Ratos , Adulto JovemRESUMO
Due to the majority of currently available genome data deriving from individuals of European ancestry, the clinical interpretation of genomic variants in individuals from diverse ethnic backgrounds remains a major diagnostic challenge. Here, we investigated the genetic cause of a complex neurodevelopmental phenotype in two Palestinian siblings. Whole exome sequencing identified a homozygous missense TECPR2 variant (Chr14(GRCh38):g.102425085G>A; NM_014844.5:c.745G>A, p.(Gly249Arg)) absent in gnomAD, segregating appropriately with the inheritance pattern in the family. Variant assessment with in silico pathogenicity prediction and protein modeling tools alongside population database frequencies led to classification as a variant of uncertain significance. As pathogenic TECPR2 variants are associated with hereditary sensory and autonomic neuropathy with intellectual disability, we reviewed previously published candidate TECPR2 missense variants to clarify clinical outcomes and variant classification using current approved guidelines, classifying a number of published variants as of uncertain significance. This work highlights genomic healthcare inequalities and the challenges in interpreting rare genetic variants in populations underrepresented in genomic databases. It also improves understanding of the clinical and genetic spectrum of TECPR2-related neuropathy and contributes to addressing genomic data disparity and inequalities of the genomic architecture in Palestinian populations.
Assuntos
Sequenciamento do Exoma , Neuropatias Hereditárias Sensoriais e Autônomas , Mutação de Sentido Incorreto , Linhagem , Irmãos , Humanos , Masculino , Feminino , Mutação de Sentido Incorreto/genética , Neuropatias Hereditárias Sensoriais e Autônomas/genética , Neuropatias Hereditárias Sensoriais e Autônomas/patologia , Neuropatias Hereditárias Sensoriais e Autônomas/diagnóstico , Fenótipo , Criança , Árabes/genética , Predisposição Genética para Doença , HomozigotoRESUMO
SLC4A10 is a plasma-membrane bound transporter that utilizes the Na+ gradient to drive cellular HCO3- uptake, thus mediating acid extrusion. In the mammalian brain, SLC4A10 is expressed in principal neurons and interneurons, as well as in epithelial cells of the choroid plexus, the organ regulating the production of CSF. Using next generation sequencing on samples from five unrelated families encompassing nine affected individuals, we show that biallelic SLC4A10 loss-of-function variants cause a clinically recognizable neurodevelopmental disorder in humans. The cardinal clinical features of the condition include hypotonia in infancy, delayed psychomotor development across all domains and intellectual impairment. Affected individuals commonly display traits associated with autistic spectrum disorder including anxiety, hyperactivity and stereotyped movements. In two cases isolated episodes of seizures were reported in the first few years of life, and a further affected child displayed bitemporal epileptogenic discharges on EEG without overt clinical seizures. While occipitofrontal circumference was reported to be normal at birth, progressive postnatal microcephaly evolved in 7 out of 10 affected individuals. Neuroradiological features included a relative preservation of brain volume compared to occipitofrontal circumference, characteristic narrow sometimes 'slit-like' lateral ventricles and corpus callosum abnormalities. Slc4a10 -/- mice, deficient for SLC4A10, also display small lateral brain ventricles and mild behavioural abnormalities including delayed habituation and alterations in the two-object novel object recognition task. Collapsed brain ventricles in both Slc4a10-/- mice and affected individuals suggest an important role of SLC4A10 in the production of the CSF. However, it is notable that despite diverse roles of the CSF in the developing and adult brain, the cortex of Slc4a10-/- mice appears grossly intact. Co-staining with synaptic markers revealed that in neurons, SLC4A10 localizes to inhibitory, but not excitatory, presynapses. These findings are supported by our functional studies, which show the release of the inhibitory neurotransmitter GABA is compromised in Slc4a10-/- mice, while the release of the excitatory neurotransmitter glutamate is preserved. Manipulation of intracellular pH partially rescues GABA release. Together our studies define a novel neurodevelopmental disorder associated with biallelic pathogenic variants in SLC4A10 and highlight the importance of further analyses of the consequences of SLC4A10 loss-of-function for brain development, synaptic transmission and network properties.
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Convulsões , Simportadores de Sódio-Bicarbonato , Criança , Camundongos , Humanos , Animais , Simportadores de Sódio-Bicarbonato/genética , Simportadores de Sódio-Bicarbonato/metabolismo , Convulsões/genética , Mutação/genética , Neurotransmissores , Ácido gama-Aminobutírico/genética , Mamíferos/metabolismo , Antiportadores de Cloreto-Bicarbonato/genética , Antiportadores de Cloreto-Bicarbonato/metabolismoRESUMO
The Rho-guanine nucleotide exchange factor (RhoGEF) TRIO acts as a key regulator of neuronal migration, axonal outgrowth, axon guidance, and synaptogenesis by activating the GTPase RAC1 and modulating actin cytoskeleton remodeling. Pathogenic variants in TRIO are associated with neurodevelopmental diseases, including intellectual disability (ID) and autism spectrum disorders (ASD). Here, we report the largest international cohort of 24 individuals with confirmed pathogenic missense or nonsense variants in TRIO. The nonsense mutations are spread along the TRIO sequence, and affected individuals show variable neurodevelopmental phenotypes. In contrast, missense variants cluster into two mutational hotspots in the TRIO sequence, one in the seventh spectrin repeat and one in the RAC1-activating GEFD1. Although all individuals in this cohort present with developmental delay and a neuro-behavioral phenotype, individuals with a pathogenic variant in the seventh spectrin repeat have a more severe ID associated with macrocephaly than do most individuals with GEFD1 variants, who display milder ID and microcephaly. Functional studies show that the spectrin and GEFD1 variants cause a TRIO-mediated hyper- or hypo-activation of RAC1, respectively, and we observe a striking correlation between RAC1 activation levels and the head size of the affected individuals. In addition, truncations in TRIO GEFD1 in the vertebrate model X. tropicalis induce defects that are concordant with the human phenotype. This work demonstrates distinct clinical and molecular disorders clustering in the GEFD1 and seventh spectrin repeat domains and highlights the importance of tight control of TRIO-RAC1 signaling in neuronal development.
Assuntos
Fatores de Troca do Nucleotídeo Guanina/genética , Mutação , Transtornos do Neurodesenvolvimento/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas rac1 de Ligação ao GTP/metabolismo , Sequência de Aminoácidos , Estudos de Coortes , Feminino , Fatores de Troca do Nucleotídeo Guanina/química , Células HEK293 , Humanos , Masculino , Fenótipo , Proteínas Serina-Treonina Quinases/química , Homologia de Sequência de AminoácidosRESUMO
PURPOSE: Transformer2 proteins (Tra2α and Tra2ß) control splicing patterns in human cells, and no human phenotypes have been associated with germline variants in these genes. The aim of this work was to associate germline variants in the TRA2B gene to a novel neurodevelopmental disorder. METHODS: A total of 12 individuals from 11 unrelated families who harbored predicted loss-of-function monoallelic variants, mostly de novo, were recruited. RNA sequencing and western blot analyses of Tra2ß-1 and Tra2ß-3 isoforms from patient-derived cells were performed. Tra2ß1-GFP, Tra2ß3-GFP and CHEK1 exon 3 plasmids were transfected into HEK-293 cells. RESULTS: All variants clustered in the 5' part of TRA2B, upstream of an alternative translation start site responsible for the expression of the noncanonical Tra2ß-3 isoform. All affected individuals presented intellectual disability and/or developmental delay, frequently associated with infantile spasms, microcephaly, brain anomalies, autism spectrum disorder, feeding difficulties, and short stature. Experimental studies showed that these variants decreased the expression of the canonical Tra2ß-1 isoform, whereas they increased the expression of the Tra2ß-3 isoform, which is shorter and lacks the N-terminal RS1 domain. Increased expression of Tra2ß-3-GFP were shown to interfere with the incorporation of CHEK1 exon 3 into its mature transcript, normally incorporated by Tra2ß-1. CONCLUSION: Predicted loss-of-function variants clustered in the 5' portion of TRA2B cause a new neurodevelopmental syndrome through an apparently dominant negative disease mechanism involving the use of an alternative translation start site and the overexpression of a shorter, repressive Tra2ß protein.
Assuntos
Transtorno do Espectro Autista , Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Humanos , Processamento Alternativo , Proteínas de Ligação a RNA/genética , Células HEK293 , Isoformas de Proteínas/genética , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Fatores de Processamento de Serina-Arginina/genética , Fatores de Processamento de Serina-Arginina/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismoRESUMO
BRD4 is part of a multiprotein complex involved in loading the cohesin complex onto DNA, a fundamental process required for cohesin-mediated loop extrusion and formation of Topologically Associating Domains. Pathogenic variations in this complex have been associated with a growing number of syndromes, collectively known as cohesinopathies, the most classic being Cornelia de Lange syndrome. However, no cohort study has been conducted to delineate the clinical and molecular spectrum of BRD4-related disorder. We formed an international collaborative study, and collected 14 new patients, including two fetuses. We performed phenotype and genotype analysis, integrated prenatal findings from fetopathological examinations, phenotypes of pediatric patients and adults. We report the first cohort of patients with BRD4-related disorder and delineate the dysmorphic features at different ages. This work extends the phenotypic spectrum of cohesinopathies and characterize a new clinically relevant and recognizable pattern, distinguishable from the other cohesinopathies.
Assuntos
Síndrome de Cornélia de Lange , Proteínas Nucleares , Proteínas de Ciclo Celular/genética , Criança , Síndrome de Cornélia de Lange/diagnóstico , Síndrome de Cornélia de Lange/genética , Síndrome de Cornélia de Lange/patologia , Feminino , Genômica , Humanos , Mutação , Proteínas Nucleares/genética , Fenótipo , Gravidez , Fatores de Transcrição/genéticaRESUMO
TAB2 is a gene located on chromosome 6q25.1 and plays a key role in development of the heart. Existing literature describes congenital heart disease as a common recognized phenotype of TAB2 gene variants, with evidence of a distinct syndromic phenotype also existing beyond this. Here we describe 14 newly identified individuals with nine novel, pathogenic TAB2 variants. The majority of individuals were identified through the Deciphering Developmental Disorders study through trio whole exome sequencing. Eight individuals had de novo variants, the other six individuals were found to have maternally inherited, or likely maternally inherited, variants. Five individuals from the same family were identified following cardiac disease gene panel in the proband and subsequent targeted familial gene sequencing. The clinical features of this cohort were compared to the existing literature. Common clinical features include distinctive facial features, growth abnormalities, joint hypermobility, hypotonia, and developmental delay. Newly identified features included feeding difficulties, sleep problems, visual problems, genitourinary abnormality, and other anatomical variations. Here we report 14 new individuals, including novel TAB2 variants, in order to expand the emerging syndromic clinical phenotype and provide further genotype-phenotype correlation.
Assuntos
Cardiopatias Congênitas , Deficiência Intelectual , Proteínas Adaptadoras de Transdução de Sinal/genética , Criança , Deficiências do Desenvolvimento/genética , Estudos de Associação Genética , Cardiopatias Congênitas/genética , Humanos , Deficiência Intelectual/genética , Fenótipo , Sequenciamento do ExomaRESUMO
SCN2A-related disorders include intellectual disability, autism spectrum disorder, seizures, episodic ataxia, and schizophrenia. In this study, the phenotype-genotype association in SCN2A-related disorders was further delineated by collecting detailed clinical and molecular characteristics. Using previously proposed genotype-phenotype hypotheses based on variant function and position, the potential of phenotype prediction from the variants found was examined. Patients were identified through the Deciphering Developmental Disorders study and gene matching strategies. Phenotypic information and variant interpretation evidence were collated. Seventeen previously unreported patients and five patients who had been previously reported (but with minimal phenotypic and segregation data) were included (10 males, 12 females; median age 10.5 years). All patients had developmental delays and the majority had intellectual disabilities. Seizures were reported in 15 of 22 (68.2%), four of 22 (18.2%) had autism spectrum disorder and no patients were reported with episodic ataxia. The majority of variants were de novo. One family had presumed gonadal mosaicism. The correlation of the use of sodium channel-blocking antiepileptic drugs with phenotype or genotype was variable. These data suggest that variant type and position alone can provide some predictive information about the phenotype in a proportion of cases, but more precise assessment of variant function is needed for meaningful phenotype prediction.
Assuntos
Transtorno do Espectro Autista , Deficiência Intelectual , Transtorno do Espectro Autista/genética , Criança , Feminino , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Masculino , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Fenótipo , Convulsões/genéticaRESUMO
Congenital diaphragmatic hernia (CDH) can occur in isolation or in conjunction with other birth defects (CDH+). A molecular etiology can only be identified in a subset of CDH cases. This is due, in part, to an incomplete understanding of the genes that contribute to diaphragm development. Here, we used clinical and molecular data from 36 individuals with CDH+ who are cataloged in the DECIPHER database to identify genes that may play a role in diaphragm development and to discover new phenotypic expansions. Among this group, we identified individuals who carried putatively deleterious sequence or copy number variants affecting CREBBP, SMARCA4, UBA2, and USP9X. The role of these genes in diaphragm development was supported by their expression in the developing mouse diaphragm, their similarity to known CDH genes using data from a previously published and validated machine learning algorithm, and/or the presence of CDH in other individuals with their associated genetic disorders. Our results demonstrate how data from DECIPHER, and other public databases, can be used to identify new phenotypic expansions and suggest that CREBBP, SMARCA4, UBA2, and USP9X play a role in diaphragm development.
Assuntos
Hérnias Diafragmáticas Congênitas , Animais , Variações do Número de Cópias de DNA , Diafragma , Hérnias Diafragmáticas Congênitas/genética , CamundongosRESUMO
PCGF2 encodes the polycomb group ring finger 2 protein, a transcriptional repressor involved in cell proliferation, differentiation, and embryogenesis. PCGF2 is a component of the polycomb repressive complex 1 (PRC1), a multiprotein complex which controls gene silencing through histone modification and chromatin remodelling. We report the phenotypic characterization of 13 patients (11 unrelated individuals and a pair of monozygotic twins) with missense mutations in PCGF2. All the mutations affected the same highly conserved proline in PCGF2 and were de novo, excepting maternal mosaicism in one. The patients demonstrated a recognizable facial gestalt, intellectual disability, feeding problems, impaired growth, and a range of brain, cardiovascular, and skeletal abnormalities. Computer structural modeling suggests the substitutions alter an N-terminal loop of PCGF2 critical for histone biding. Mutant PCGF2 may have dominant-negative effects, sequestering PRC1 components into complexes that lack the ability to interact efficiently with histones. These findings demonstrate the important role of PCGF2 in human development and confirm that heterozygous substitutions of the Pro65 residue of PCGF2 cause a recognizable syndrome characterized by distinctive craniofacial, neurological, cardiovascular, and skeletal features.
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The tRNA synthetases catalyze the first step of protein synthesis and have increasingly been studied for their nuclear and extra-cellular ex-translational activities. Human genetic conditions such as Charcot-Marie-Tooth have been attributed to dominant gain-of-function mutations in some tRNA synthetases. Unlike dominantly inherited gain-of-function mutations, recessive loss-of-function mutations can potentially elucidate ex-translational activities. We present here five individuals from four families with a multi-system disease associated with bi-allelic mutations in FARSB that encodes the beta chain of the alpha2beta2 phenylalanine-tRNA synthetase (FARS). Collectively, the mutant alleles encompass a 5'-splice junction non-coding variant (SJV) and six missense variants, one of which is shared by unrelated individuals. The clinical condition is characterized by interstitial lung disease, cerebral aneurysms and brain calcifications, and cirrhosis. For the SJV, we confirmed exon skipping leading to a frameshift associated with noncatalytic activity. While the bi-allelic combination of the SJV with a p.Arg305Gln missense mutation in two individuals led to severe disease, cells from neither the asymptomatic heterozygous carriers nor the compound heterozygous affected individual had any defect in protein synthesis. These results support a disease mechanism independent of tRNA synthetase activities in protein translation and suggest that this FARS activity is essential for normal function in multiple organs.
Assuntos
Aminoacil-tRNA Sintetases/genética , Pneumopatias/genética , Mutação/genética , Adolescente , Alelos , Doença de Charcot-Marie-Tooth/genética , Pré-Escolar , Feminino , Genes Recessivos/genética , Heterozigoto , Humanos , Lactente , Masculino , Biossíntese de Proteínas/genéticaRESUMO
PURPOSE: We describe a novel neurobehavioral phenotype of autism spectrum disorder (ASD), intellectual disability, and/or attention-deficit/hyperactivity disorder (ADHD) associated with de novo or inherited deleterious variants in members of the RFX family of genes. RFX genes are evolutionarily conserved transcription factors that act as master regulators of central nervous system development and ciliogenesis. METHODS: We assembled a cohort of 38 individuals (from 33 unrelated families) with de novo variants in RFX3, RFX4, and RFX7. We describe their common clinical phenotypes and present bioinformatic analyses of expression patterns and downstream targets of these genes as they relate to other neurodevelopmental risk genes. RESULTS: These individuals share neurobehavioral features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. CONCLUSION: These results establish a likely role of deleterious variation in RFX3, RFX4, and RFX7 in cases of monogenic intellectual disability, ADHD and ASD, and position these genes as potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Transtorno do Espectro Autista , Transtorno Autístico , Deficiência Intelectual , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Espectro Autista/genética , Transtorno Autístico/genética , Humanos , Deficiência Intelectual/genética , Fatores de Transcrição de Fator Regulador X , Fatores de Transcrição/genéticaRESUMO
Smith-Kingsmore Syndrome (SKS) is a rare genetic syndrome associated with megalencephaly, a variable intellectual disability, autism spectrum disorder, and MTOR gain of function variants. Only 30 patients with MTOR missense variants are published, including 14 (47%) with the MTOR c.5395G>A p.(Glu1799Lys) variant. Limited phenotypic data impacts the quality of information delivered to families and the robustness of interpretation of novel MTOR missense variation. This study aims to improve our understanding of the SKS phenotype through the investigation of 16 further patients with the MTOR c.5395G>A p.(Glu1799Lys) variant. Through the careful phenotypic evaluation of these 16 patients and integration with data from 14 previously reported patients, we have defined major (100% patients) and frequent (>15%) SKS clinical characteristics and, using these data, proposed guidance for evidence-based management. In addition, in the absence of functional studies, we suggest that the combination of the SKS major clinical features of megalencephaly (where the head circumference is at least 3SD) and an intellectual disability with a de novo MTOR missense variant (absent from population databases) should be considered diagnostic for SKS.
Assuntos
Alelos , Estudos de Associação Genética , Mutação de Sentido Incorreto , Fenótipo , Serina-Treonina Quinases TOR/genética , Adolescente , Substituição de Aminoácidos , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/genética , Criança , Pré-Escolar , Fácies , Feminino , Loci Gênicos , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Masculino , Megalencefalia/diagnóstico , Megalencefalia/genética , SíndromeRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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PURPOSE: Sifrim-Hitz-Weiss syndrome (SIHIWES) is a recently described multisystemic neurodevelopmental disorder caused by de novo variants inCHD4. In this study, we investigated the clinical spectrum of the disorder, genotype-phenotype correlations, and the effect of different missense variants on CHD4 function. METHODS: We collected clinical and molecular data from 32 individuals with mostly de novo variants in CHD4, identified through next-generation sequencing. We performed adenosine triphosphate (ATP) hydrolysis and nucleosome remodeling assays on variants from five different CHD4 domains. RESULTS: The majority of participants had global developmental delay, mild to moderate intellectual disability, brain anomalies, congenital heart defects, and dysmorphic features. Macrocephaly was a frequent but not universal finding. Additional common abnormalities included hypogonadism in males, skeletal and limb anomalies, hearing impairment, and ophthalmic abnormalities. The majority of variants were nontruncating and affected the SNF2-like region of the protein. We did not identify genotype-phenotype correlations based on the type or location of variants. Alterations in ATP hydrolysis and chromatin remodeling activities were observed in variants from different domains. CONCLUSION: The CHD4-related syndrome is a multisystemic neurodevelopmental disorder. Missense substitutions in different protein domains alter CHD4 function in a variant-specific manner, but result in a similar phenotype in humans.
Assuntos
Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/genética , Transtornos do Neurodesenvolvimento/genética , Anormalidades Múltiplas/genética , Adolescente , Adulto , Criança , Pré-Escolar , Montagem e Desmontagem da Cromatina/genética , Deficiências do Desenvolvimento/genética , Feminino , Estudos de Associação Genética , Genótipo , Perda Auditiva/genética , Cardiopatias Congênitas/genética , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/genética , Masculino , Megalencefalia/genética , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/metabolismo , Anormalidades Musculoesqueléticas/genética , Mutação de Sentido Incorreto/genética , Fenótipo , Síndrome , Fatores de Transcrição/genéticaRESUMO
Primrose syndrome (PS; MIM# 259050) is characterized by intellectual disability (ID), macrocephaly, unusual facial features (frontal bossing, deeply set eyes, down-slanting palpebral fissures), calcified external ears, sparse body hair and distal muscle wasting. The syndrome is caused by de novo heterozygous missense variants in ZBTB20. Most of the 29 published patients are adults as characteristics appear more recognizable with age. We present 13 hitherto unpublished individuals and summarize the clinical and molecular findings in all 42 patients. Several signs and symptoms of PS develop during childhood, but the cardinal features, such as calcification of the external ears, cystic bone lesions, muscle wasting, and contractures typically develop between 10 and 16 years of age. Biochemically, anemia and increased alpha-fetoprotein levels are often present. Two adult males with PS developed a testicular tumor. Although PS should be regarded as a progressive entity, there are no indications that cognition becomes more impaired with age. No obvious genotype-phenotype correlation is present. A subgroup of patients with ZBTB20 variants may be associated with mild, nonspecific ID. Metabolic investigations suggest a disturbed mitochondrial fatty acid oxidation. We suggest a regular surveillance in all adult males with PS until it is clear whether or not there is a truly elevated risk of testicular cancer.
Assuntos
Anormalidades Múltiplas/genética , Calcinose/genética , Otopatias/genética , Predisposição Genética para Doença , Deficiência Intelectual/genética , Megalencefalia/genética , Atrofia Muscular/genética , Proteínas do Tecido Nervoso/genética , Fatores de Transcrição/genética , 3-Hidroxiacil-CoA Desidrogenases/genética , Anormalidades Múltiplas/patologia , Acetil-CoA C-Aciltransferase/genética , Adolescente , Adulto , Calcinose/patologia , Isomerases de Ligação Dupla Carbono-Carbono/genética , Criança , Pré-Escolar , Otopatias/patologia , Enoil-CoA Hidratase/genética , Face/anormalidades , Feminino , Estudos de Associação Genética , Heterozigoto , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Megalencefalia/patologia , Pessoa de Meia-Idade , Mitocôndrias/genética , Mitocôndrias/patologia , Atrofia Muscular/patologia , Mutação , Mutação de Sentido Incorreto/genética , Fenótipo , Racemases e Epimerases/genética , Neoplasias Testiculares , Adulto JovemRESUMO
We present the case of a male who shortly after birth developed acute respiratory distress due to bilateral choanal atresia, following which he was found to have rectal stenosis. Genetic testing for CHARGE syndrome was negative, but whole genome sequencing identified heterozygosity for a pathogenic missense variant in TP63 (c.727C > T, p.(Arg243Trp). He also has partial cutaneous syndactyly of the third and fourth fingers of the right hand, and bilateral lacrimal duct stenosis/aplasia. A later maxillofacial review identified a palpable submucousal cleft and his scalp hair is blond and slightly sparse. Choanal atresia and rectal stenosis are recognized features of ectrodactyly-ectodermal dysplasia-clefting syndrome, but we believe this is the first report of a case presenting with these features in the absence of the cardinal features.
Assuntos
Atresia das Cóanas/genética , Fenda Labial/genética , Fissura Palatina/genética , Displasia Ectodérmica/genética , Doenças Retais/genética , Síndrome do Desconforto Respiratório/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Síndrome CHARGE/diagnóstico , Síndrome CHARGE/genética , Síndrome CHARGE/patologia , Atresia das Cóanas/complicações , Atresia das Cóanas/diagnóstico , Atresia das Cóanas/patologia , Fenda Labial/complicações , Fenda Labial/diagnóstico , Fenda Labial/patologia , Fissura Palatina/complicações , Fissura Palatina/diagnóstico , Fissura Palatina/patologia , Constrição Patológica/complicações , Constrição Patológica/diagnóstico , Constrição Patológica/genética , Constrição Patológica/patologia , Displasia Ectodérmica/complicações , Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica/patologia , Predisposição Genética para Doença , Deformidades Congênitas da Mão/genética , Deformidades Congênitas da Mão/patologia , Heterozigoto , Humanos , Lactente , Masculino , Mutação de Sentido Incorreto/genética , Doenças Retais/complicações , Doenças Retais/diagnóstico , Doenças Retais/patologia , Síndrome do Desconforto Respiratório/complicações , Síndrome do Desconforto Respiratório/diagnóstico , Síndrome do Desconforto Respiratório/patologia , Sequenciamento Completo do GenomaRESUMO
Familial amniotic band sequence (ABS) is rare but has been reported in the offspring of mothers with connective tissue disorders. We present a family of two half-siblings with ABS who share the same biological father. Following a serious vascular event a de novo pathogenic variant in COL3A1 was detected in the father, confirming a diagnosis of vascular Ehlers-Danlos syndrome (vEDS). The same variant was found in both his ABS-affected children but not in his unaffected child. The amniotic membrane is derived from fetal tissue, type III collagen being a component. As the affected children are paternal half-siblings, ABS was less likely due to maternal factors. Rather, the amniotic bands may have resulted from decreased type III collagen production as seen in people with vEDS, causing fragility of the amniotic membrane. Consequently, it is important to consider vEDS in patients with ABS.
Assuntos
Síndrome de Bandas Amnióticas/genética , Colágeno Tipo III/genética , Síndrome de Ehlers-Danlos/genética , Adulto , Síndrome de Bandas Amnióticas/complicações , Síndrome de Bandas Amnióticas/diagnóstico , Síndrome de Bandas Amnióticas/patologia , Criança , Doenças do Tecido Conjuntivo/complicações , Doenças do Tecido Conjuntivo/diagnóstico , Doenças do Tecido Conjuntivo/genética , Doenças do Tecido Conjuntivo/patologia , Síndrome de Ehlers-Danlos/complicações , Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/patologia , Feminino , Humanos , Recém-Nascido , Masculino , Mutação/genética , Herança Paterna/genética , Fenótipo , IrmãosRESUMO
With advances in genetic testing and improved access to such advances, whole exome sequencing is becoming a first-line investigation in clinical work-up of children with developmental delay/intellectual disability (ID). As a result, the need to understand the importance of genetic variants and its effect on the clinical phenotype is increasing. Here, we report on the largest cohort of patients with HNRNPU variants. These 21 patients follow on from the previous study published by Yates et al. in 2017 from our group predominantly identified from the Deciphering Developmental Disorders study that reported seven patients with HNRNPU variants. All the probands reported here have a de novo loss-of-function variant. These probands have craniofacial dysmorphic features, in the majority including widely spaced teeth, microcephaly, high arched eyebrows, and palpebral fissure abnormalities. Many of the patients in the group also have moderate to severe ID and seizures that tend to start in early childhood. This series has allowed us to define a novel neurodevelopmental syndrome, with a likely mechanism of haploinsufficiency, and expand substantially on already published literature on HNRNPU-related neurodevelopmental syndrome.