RESUMEN
Neurodevelopmental disorders (NDDs) result from highly penetrant variation in hundreds of different genes, some of which have not yet been identified. Using the MatchMaker Exchange, we assembled a cohort of 27 individuals with rare, protein-altering variation in the transcriptional coregulator ZMYM3, located on the X chromosome. Most (n = 24) individuals were males, 17 of which have a maternally inherited variant; six individuals (4 male, 2 female) harbor de novo variants. Overlapping features included developmental delay, intellectual disability, behavioral abnormalities, and a specific facial gestalt in a subset of males. Variants in almost all individuals (n = 26) are missense, including six that recurrently affect two residues. Four unrelated probands were identified with inherited variation affecting Arg441, a site at which variation has been previously seen in NDD-affected siblings, and two individuals have de novo variation resulting in p.Arg1294Cys (c.3880C>T). All variants affect evolutionarily conserved sites, and most are predicted to damage protein structure or function. ZMYM3 is relatively intolerant to variation in the general population, is widely expressed across human tissues, and encodes a component of the KDM1A-RCOR1 chromatin-modifying complex. ChIP-seq experiments on one variant, p.Arg1274Trp, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect. While we are unable to perform statistical evaluations to definitively support a causative role for variation in ZMYM3, the totality of the evidence, including 27 affected individuals, recurrent variation at two codons, overlapping phenotypic features, protein-modeling data, evolutionary constraint, and experimentally confirmed functional effects strongly support ZMYM3 as an NDD-associated gene.
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Discapacidad Intelectual , Malformaciones del Sistema Nervioso , Trastornos del Neurodesarrollo , Humanos , Masculino , Femenino , Trastornos del Neurodesarrollo/genética , Discapacidad Intelectual/genética , Fenotipo , Regulación de la Expresión Génica , Cara , Proteínas Nucleares/genética , Histona Demetilasas/genéticaRESUMEN
Chromatin is essentially an array of nucleosomes, each of which consists of the DNA double-stranded fiber wrapped around a histone octamer. This organization supports cellular processes such as DNA replication, DNA transcription, and DNA repair in all eukaryotes. Human histone H4 is encoded by fourteen canonical histone H4 genes, all differing at the nucleotide level but encoding an invariant protein. Here, we present a cohort of 29 subjects with de novo missense variants in six H4 genes (H4C3, H4C4, H4C5, H4C6, H4C9, and H4C11) identified by whole-exome sequencing and matchmaking. All individuals present with neurodevelopmental features of intellectual disability and motor and/or gross developmental delay, while non-neurological features are more variable. Ten amino acids are affected, six recurrently, and are all located within the H4 core or C-terminal tail. These variants cluster to specific regions of the core H4 globular domain, where protein-protein interactions occur with either other histone subunits or histone chaperones. Functional consequences of the identified variants were evaluated in zebrafish embryos, which displayed abnormal general development, defective head organs, and reduced body axis length, providing compelling evidence for the causality of the reported disorder(s). While multiple developmental syndromes have been linked to chromatin-associated factors, missense-bearing histone variants (e.g., H3 oncohistones) are only recently emerging as a major cause of pathogenicity. Our findings establish a broader involvement of H4 variants in developmental syndromes.
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Histonas , Pez Cebra , Animales , Cromatina , ADN , Histonas/metabolismo , Humanos , Síndrome , Pez Cebra/genética , Pez Cebra/metabolismoRESUMEN
PURPOSE: Critically ill infants from marginalized populations disproportionately receive care in neonatal intensive care units (NICUs) that lack access to state-of-the-art genomic care, leading to inequitable outcomes. We sought provider perspectives to inform our implementation study (VIGOR) providing rapid genomic sequencing within these settings. METHODS: We conducted semistructured focus groups with neonatal and genetics providers at 6 NICUs at safety-net hospitals, informed by the Promoting Action on Research Implementation in Health Services framework, which incorporates evidence, context, and facilitation domains. We iteratively developed codes and themes until thematic saturation was reached. RESULTS: Regarding evidence, providers felt that genetic testing benefits infants and families. Regarding context, the major barriers identified to genomic care were genetic testing cost, lack of genetics expertise for disclosure and follow-up, and navigating the complexity of selecting and ordering genetic tests. Providers had negative feelings about the current status quo and inequity in genomic care across NICUs. Regarding facilitation, providers felt that a virtual support model such as VIGOR would address major barriers and foster family-centered care and collaboration. CONCLUSION: NICU providers at safety-net hospitals believe that access to state-of-the-art genomic care is critical for optimizing infant outcomes; yet, substantial barriers exist that the VIGOR study may address.
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SWI/SNF-related intellectual disability disorders (SSRIDDs) are rare neurodevelopmental disorders characterized by developmental disability, coarse facial features, and fifth digit/nail hypoplasia that are caused by pathogenic variants in genes that encode for members of the SWI/SNF (or BAF) family of chromatin remodeling complexes. We have identified 12 individuals with rare variants (10 loss-of-function, 2 missense) in the BICRA (BRD4 interacting chromatin remodeling complex-associated protein) gene, also known as GLTSCR1, which encodes a subunit of the non-canonical BAF (ncBAF) complex. These individuals exhibited neurodevelopmental phenotypes that include developmental delay, intellectual disability, autism spectrum disorder, and behavioral abnormalities as well as dysmorphic features. Notably, the majority of individuals lack the fifth digit/nail hypoplasia phenotype, a hallmark of most SSRIDDs. To confirm the role of BICRA in the development of these phenotypes, we performed functional characterization of the zebrafish and Drosophila orthologs of BICRA. In zebrafish, a mutation of bicra that mimics one of the loss-of-function variants leads to craniofacial defects possibly akin to the dysmorphic facial features seen in individuals harboring putatively pathogenic BICRA variants. We further show that Bicra physically binds to other non-canonical ncBAF complex members, including the BRD9/7 ortholog, CG7154, and is the defining member of the ncBAF complex in flies. Like other SWI/SNF complex members, loss of Bicra function in flies acts as a dominant enhancer of position effect variegation but in a more context-specific manner. We conclude that haploinsufficiency of BICRA leads to a unique SSRIDD in humans whose phenotypes overlap with those previously reported.
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Proteínas Cromosómicas no Histona/genética , Discapacidades del Desarrollo/genética , Mutación Missense , Fenotipo , Proteínas Supresoras de Tumor/genética , Adolescente , Animales , Niño , Preescolar , Proteínas de Drosophila/genética , Drosophila melanogaster , Femenino , Genes Dominantes , Variación Genética , Haploinsuficiencia , Humanos , Lactante , Masculino , Microscopía Confocal , Neuroglía/metabolismo , Neuronas/metabolismo , Unión Proteica , Pez Cebra , Proteínas de Pez Cebra/genéticaRESUMEN
PURPOSE: ZMYND8 encodes a multidomain protein that serves as a central interactive hub for coordinating critical roles in transcription regulation, chromatin remodeling, regulation of super-enhancers, DNA damage response and tumor suppression. We delineate a novel neurocognitive disorder caused by variants in the ZMYND8 gene. METHODS: An international collaboration, exome sequencing, molecular modeling, yeast two-hybrid assays, analysis of available transcriptomic data and a knockdown Drosophila model were used to characterize the ZMYND8 variants. RESULTS: ZMYND8 variants were identified in 11 unrelated individuals; 10 occurred de novo and one suspected de novo; 2 were truncating, 9 were missense, of which one was recurrent. The disorder is characterized by intellectual disability with variable cardiovascular, ophthalmologic and minor skeletal anomalies. Missense variants in the PWWP domain of ZMYND8 abolish the interaction with Drebrin and missense variants in the MYND domain disrupt the interaction with GATAD2A. ZMYND8 is broadly expressed across cell types in all brain regions and shows highest expression in the early stages of brain development. Neuronal knockdown of the DrosophilaZMYND8 ortholog results in decreased habituation learning, consistent with a role in cognitive function. CONCLUSION: We present genomic and functional evidence for disruption of ZMYND8 as a novel etiology of syndromic intellectual disability.
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Discapacidad Intelectual , Trastornos del Neurodesarrollo , Encéfalo/metabolismo , Regulación de la Expresión Génica , Humanos , Discapacidad Intelectual/genética , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/metabolismo , Dominios Proteicos , Secuenciación del ExomaRESUMEN
The nuclear factor I (NFI) family of transcription factors play an important role in normal development of multiple organs. Three NFI family members are highly expressed in the brain, and deletions or sequence variants in two of these, NFIA and NFIX, have been associated with intellectual disability (ID) and brain malformations. NFIB, however, has not previously been implicated in human disease. Here, we present a cohort of 18 individuals with mild ID and behavioral issues who are haploinsufficient for NFIB. Ten individuals harbored overlapping microdeletions of the chromosomal 9p23-p22.2 region, ranging in size from 225 kb to 4.3 Mb. Five additional subjects had point sequence variations creating a premature termination codon, and three subjects harbored single-nucleotide variations resulting in an inactive protein as determined using an in vitro reporter assay. All individuals presented with additional variable neurodevelopmental phenotypes, including muscular hypotonia, motor and speech delay, attention deficit disorder, autism spectrum disorder, and behavioral abnormalities. While structural brain anomalies, including dysgenesis of corpus callosum, were variable, individuals most frequently presented with macrocephaly. To determine whether macrocephaly could be a functional consequence of NFIB disruption, we analyzed a cortex-specific Nfib conditional knockout mouse model, which is postnatally viable. Utilizing magnetic resonance imaging and histology, we demonstrate that Nfib conditional knockout mice have enlargement of the cerebral cortex but preservation of overall brain structure and interhemispheric connectivity. Based on our findings, we propose that haploinsufficiency of NFIB causes ID with macrocephaly.
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Haploinsuficiencia/genética , Discapacidad Intelectual/genética , Megalencefalia/genética , Factores de Transcripción NFI/genética , Adolescente , Adulto , Animales , Corteza Cerebral/patología , Niño , Preescolar , Codón sin Sentido/genética , Estudios de Cohortes , Cuerpo Calloso/patología , Femenino , Humanos , Masculino , Ratones , Ratones Noqueados , Polimorfismo de Nucleótido Simple/genética , Adulto JovenRESUMEN
PURPOSE: In this study we investigate the disease etiology in 12 patients with de novo variants in FAR1 all resulting in an amino acid change at position 480 (p.Arg480Cys/His/Leu). METHODS: Following next-generation sequencing and clinical phenotyping, functional characterization was performed in patients' fibroblasts using FAR1 enzyme analysis, FAR1 immunoblotting/immunofluorescence, and lipidomics. RESULTS: All patients had spastic paraparesis and bilateral congenital/juvenile cataracts, in most combined with speech and gross motor developmental delay and truncal hypotonia. FAR1 deficiency caused by biallelic variants results in defective ether lipid synthesis and plasmalogen deficiency. In contrast, patients' fibroblasts with the de novo FAR1 variants showed elevated plasmalogen levels. Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogen-dependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production. CONCLUSION: Heterozygous de novo variants affecting the Arg480 residue of FAR1 lead to an autosomal dominant disorder with a different disease mechanism than that of recessive FAR1 deficiency and a diametrically opposed biochemical phenotype. Our findings show that for patients with spastic paraparesis and bilateral cataracts, FAR1 should be considered as a candidate gene and added to gene panels for hereditary spastic paraplegia, cerebral palsy, and juvenile cataracts.
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Aldehído Oxidorreductasas/genética , Éteres , Lípidos , Paraplejía Espástica Hereditaria/genética , Humanos , FenotipoRESUMEN
Degradation of proteins by the ubiquitin-proteasome system (UPS) is an essential biological process in the development of eukaryotic organisms. Dysregulation of this mechanism leads to numerous human neurodegenerative or neurodevelopmental disorders. Through a multi-center collaboration, we identified six de novo genomic deletions and four de novo point mutations involving PSMD12, encoding the non-ATPase subunit PSMD12 (aka RPN5) of the 19S regulator of 26S proteasome complex, in unrelated individuals with intellectual disability, congenital malformations, ophthalmologic anomalies, feeding difficulties, deafness, and subtle dysmorphic facial features. We observed reduced PSMD12 levels and an accumulation of ubiquitinated proteins without any impairment of proteasome catalytic activity. Our PSMD12 loss-of-function zebrafish CRISPR/Cas9 model exhibited microcephaly, decreased convolution of the renal tubules, and abnormal craniofacial morphology. Our data support the biological importance of PSMD12 as a scaffolding subunit in proteasome function during development and neurogenesis in particular; they enable the definition of a neurodevelopmental disorder due to PSMD12 variants, expanding the phenotypic spectrum of UPS-dependent disorders.
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Trastornos del Neurodesarrollo/genética , Complejo de la Endopetidasa Proteasomal/genética , Adolescente , Animales , Niño , Preescolar , Variaciones en el Número de Copia de ADN , Modelos Animales de Enfermedad , Regulación hacia Abajo , Femenino , Eliminación de Gen , Humanos , Lactante , Discapacidad Intelectual/genética , Masculino , Microcefalia/genética , Polimorfismo de Nucleótido Simple , Pez Cebra/genéticaRESUMEN
Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway.
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Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/genética , Discapacidad Intelectual/genética , Mutación/genética , Animales , Encéfalo/patología , Línea Celular , Exoma/genética , Femenino , Ácido Glutámico/genética , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/patología , Fosforilación/genética , Transducción de Señal/genéticaRESUMEN
Whole-exome sequencing (WES) is increasingly being utilized to diagnose individuals with undiagnosed disorders. Developmental delay and short stature are common clinical indications for WES. We performed WES in three families, using proband-parent trios and two additional affected siblings. We identified a syndrome due to an autosomal-recessively inherited deficiency of transketolase, encoded by TKT, on chromosome 3p21. Our series includes three families with a total of five affected individuals, ranging in age from 4 to 25 years. Two families of Ashkenazi Jewish ancestry were homozygous for an 18 base pair in-frame insertion in TKT. The third family was compound heterozygous for nonsense and missense variants in TKT. All affected individuals had short stature and were developmentally delayed. Congenital heart defects were noted in four of the five affected individuals, and there was a history of chronic diarrhea and cataracts in the older individuals with the homozygous 18 base pair insertion. Enzymatic testing confirmed significantly reduced transketolase activity. Elevated urinary excretion of erythritol, arabitol, ribitol, and pent(ul)ose-5-phosphates was detected, as well as elevated amounts of erythritol, arabitol, and ribitol in the plasma of affected individuals. Transketolase deficiency reduces NADPH synthesis and nucleic acid synthesis and cell division and could explain the problems with growth. NADPH is also critical for maintaining cerebral glutathione, which might contribute to the neurodevelopmental delays. Transketolase deficiency is one of a growing list of inborn errors of metabolism in the non-oxidative part of the pentose phosphate pathway.
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Discapacidades del Desarrollo/etiología , Enanismo/etiología , Cardiopatías Congénitas/etiología , Mutación/genética , Transcetolasa/genética , Adulto , Niño , Preescolar , Discapacidades del Desarrollo/metabolismo , Discapacidades del Desarrollo/patología , Enanismo/metabolismo , Enanismo/patología , Femenino , Glutatión/metabolismo , Cardiopatías Congénitas/metabolismo , Cardiopatías Congénitas/patología , Humanos , Masculino , NADP/metabolismo , Linaje , Síndrome , Adulto JovenRESUMEN
Early-onset epileptic encephalopathy (EOEE) represents a heterogeneous group of severe disorders characterized by seizures, interictal epileptiform activity with a disorganized electroencephalography background, developmental regression or retardation, and onset before 1 year of age. Among a cohort of 57 individuals with epileptic encephalopathy, we ascertained two unrelated affected individuals with EOEE associated with developmental impairment and autosomal-recessive variants in AP3B2 by means of whole-exome sequencing. The targeted sequencing of AP3B2 in 86 unrelated individuals with EOEE led to the identification of an additional family. We gathered five additional families with eight affected individuals through the Matchmaker Exchange initiative by matching autosomal-recessive mutations in AP3B2. Reverse phenotyping of 12 affected individuals from eight families revealed a homogeneous EOEE phenotype characterized by severe developmental delay, poor visual contact with optic atrophy, and postnatal microcephaly. No spasticity, albinism, or hematological symptoms were reported. AP3B2 encodes the neuron-specific subunit of the AP-3 complex. Autosomal-recessive variations of AP3B1, the ubiquitous isoform, cause Hermansky-Pudlak syndrome type 2. The only isoform for the δ subunit of the AP-3 complex is encoded by AP3D1. Autosomal-recessive mutations in AP3D1 cause a severe disorder cumulating the symptoms of the AP3B1 and AP3B2 defects.
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Complejo 3 de Proteína Adaptadora/genética , Subunidades beta de Complejo de Proteína Adaptadora/genética , Epilepsia/complicaciones , Epilepsia/genética , Genes Recesivos/genética , Mutación , Atrofia Óptica/complicaciones , Atrofia Óptica/genética , Edad de Inicio , Niño , Preescolar , Discapacidades del Desarrollo/genética , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Microcefalia/genética , Linaje , SíndromeRESUMEN
Highly conserved TREX-mediated mRNA export is emerging as a key pathway in neuronal development and differentiation. TREX subunit variants cause neurodevelopmental disorders (NDDs) by interfering with mRNA export from the cell nucleus to the cytoplasm. Previously we implicated four missense variants in the X-linked THOC2 gene in intellectual disability (ID). We now report an additional six affected individuals from five unrelated families with two de novo and three maternally inherited pathogenic or likely pathogenic variants in THOC2 extending the genotypic and phenotypic spectrum. These comprise three rare missense THOC2 variants that affect evolutionarily conserved amino acid residues and reduce protein stability and two with canonical splice-site THOC2 variants that result in C-terminally truncated THOC2 proteins. We present detailed clinical assessment and functional studies on a de novo variant in a female with an epileptic encephalopathy and discuss an additional four families with rare variants in THOC2 with supportive evidence for pathogenicity. Severe neurocognitive features, including movement and seizure disorders, were observed in this cohort. Taken together our data show that even subtle alterations to the canonical molecular pathways such as mRNA export, otherwise essential for cellular life, can be compatible with life, but lead to NDDs in humans.
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Epilepsia/metabolismo , Exones/genética , Trastornos del Crecimiento/metabolismo , Discapacidad Intelectual/metabolismo , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/metabolismo , Niño , Preescolar , Epilepsia/genética , Femenino , Trastornos del Crecimiento/genética , Células HEK293 , Células HeLa , Humanos , Discapacidad Intelectual/genética , Masculino , Mutación Missense/genética , Isoformas de Proteínas/genética , Transporte de ARN/genética , Transporte de ARN/fisiología , Proteínas de Unión al ARN/genéticaRESUMEN
BACKGROUND: Rumination predicts depression in adults and adolescents. The development of rumination has been linked to parenting practices, but only limited research has investigated this and research has tended to rely on self-report parenting measures. AIMS: To investigate the relationship between female adolescent rumination and maternal modelling, criticism and positivity using an observational measure of parental behaviour. METHOD: A cross-sectional design was used. Daughters aged 16-18 years and their mothers (n = 154 dyads) completed questionnaire measures of rumination and affect. Mothers of girls with rumination scores in the upper and lower quartile (both n = 26) also completed the Five Minute Speech Sample, which was used to measure maternal criticism and positivity. RESULTS: Mothers of low rumination girls made significantly more positive comments about their daughters than the mothers of high ruminators. Mothers made very few critical comments. Self-reported rumination was not correlated in mothers and daughters, suggesting a lack of support for the potential role of modelling. CONCLUSION: Overall, low maternal positivity was associated with rumination in female adolescents. There was no evidence that maternal rumination or criticism were associated with adolescent rumination. The results suggest a number of implications for future research, including the need for prospective longitudinal studies using observational parenting measures.
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Madres/psicología , Responsabilidad Parental/psicología , Psicología del Adolescente , Rumiación Cognitiva , Adolescente , Afecto , Estudios Transversales , Femenino , Humanos , Autoinforme , Encuestas y CuestionariosRESUMEN
One of the goals of evaluating a patient in the genetics clinic is to find the diagnosis that would explain his or her clinical presentation. Sometimes the patient's diagnosis remains undefined or does not explain all of the clinical findings. As clinicians are often guided by a "single disorder" paradigm, diagnosing multiple genetic conditions in the same patient requires a heightened sense of awareness. Over the last few years, we evaluated several patients (n = 14) who were found to have more than one genetic diagnosis. In this paper, we will describe their natural history and diagnoses, and draw on the lessons learned from this phenomenon, which we expect to grow in this era of next-generation diagnostic technologies. To our knowledge, this is by far the largest series of patients with double diagnoses. Based on our findings, we strongly recommend that physicians question every diagnosis to determine whether it indeed explains all of the patients' symptoms, and consider whether they should continue the diagnostic evaluation to look for a more accurate and complete set of diagnoses. © 2016 Wiley Periodicals, Inc.
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Estudios de Asociación Genética , Enfermedades Genéticas Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/genética , Adolescente , Adulto , Aneuploidia , Niño , Preescolar , Deleción Cromosómica , Duplicación Cromosómica , Toma de Decisiones Clínicas , Femenino , Enfermedades Genéticas Congénitas/terapia , Pruebas Genéticas , Variación Genética , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Factores de Riesgo , Adulto JovenRESUMEN
In this study, the cytotoxicity of two different crystal phases of TiO2 nanoparticles, with surface modification by humic acid (HA), to Escherichia coli, was assessed. The physicochemical properties of TiO2 nanoparticles were thoroughly characterized. Three different initial concentrations, namely 50, 100, and 200 ppm, of HA were used for synthesis of HA coated TiO2 nanoparticles (denoted as A/RHA50, A/RHA100, and A/RHA200, respectively). Results indicate that rutile (LC50 (concentration that causes 50% mortality compared the control group)=6.5) was more toxic than anatase (LC50=278.8) under simulated sunlight (SSL) irradiation, possibly due to an extremely narrow band gap. It is noted that HA coating increased the toxicity of anatase, but decreased that of rutile. Additionally, AHA50 and RHA50 had the biggest differences compared to uncoated anatase and rutile with LC50 of 201.9 and 21.6, respectively. We then investigated the formation of reactive oxygen species (ROS) by TiO2 nanoparticles in terms of hydroxyl radicals (·OH) and superoxide anions (O2(·-)). Data suggested that O2(·-) was the main ROS that accounted for the higher toxicity of rutile upon SSL irradiation. We also observed that HA coating decreased the generation of ·OH and O2(·-) on rutile, but increased O2(·-) formation on anatase. Results from TEM analysis also indicated that HA coated rutile tended to be attached to the surface of E. coli more than anatase.
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Sustancias Húmicas , Nanopartículas del Metal/toxicidad , Titanio/toxicidad , Escherichia coli/efectos de los fármacos , Nanopartículas del Metal/química , Especies Reactivas de Oxígeno , Titanio/químicaRESUMEN
Interfaces between organic electron-donating (D) and electron-accepting (A) materials have the ability to generate charge carriers on illumination. Efficient organic solar cells require a high yield for this process, combined with a minimum of energy losses. Here, we investigate the role of the lowest energy emissive interfacial charge-transfer state (CT1) in the charge generation process. We measure the quantum yield and the electric field dependence of charge generation on excitation of the charge-transfer (CT) state manifold via weakly allowed, low-energy optical transitions. For a wide range of photovoltaic devices based on polymer:fullerene, small-molecule:C60 and polymer:polymer blends, our study reveals that the internal quantum efficiency (IQE) is essentially independent of whether or not D, A or CT states with an energy higher than that of CT1 are excited. The best materials systems show an IQE higher than 90% without the need for excess electronic or vibrational energy.
RESUMEN
The SATB2-associated syndrome (SAS) was recently proposed as a clinically recognizable syndrome that results from deleterious alterations of the SATB2 gene in humans. Although interstitial deletions at 2q33 encompassing SATB2, either alone or contiguously with other genes, have been reported before, there is limited literature regarding intragenic mutations of this gene and the resulting phenotype. We describe five patients in whom whole exome sequencing identified five unique de novo mutations in the SATB2 gene (one splice site, one frameshift, and three nonsense mutations). The five patients had overlapping features that support the characteristic features of the SAS: intellectual disability with limited speech development and craniofacial abnormalities including cleft palate, dysmorphic features, and dental abnormalities. Furthermore, Patient 1 also had features not previously described that represent an expansion of the phenotype. Osteopenia was seen in two of the patients, suggesting that this finding could be added to the list of distinctive findings. We provide supporting evidence that analysis for deletions or point mutations in SATB2 should be considered in children with intellectual disability and severely impaired speech, cleft or high palate, teeth abnormalities, and osteopenia.
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Anomalías Craneofaciales/genética , Discapacidad Intelectual/genética , Trastornos del Desarrollo del Lenguaje/genética , Proteínas de Unión a la Región de Fijación a la Matriz/genética , Factores de Transcripción/genética , Adulto , Niño , Preescolar , Cromosomas Humanos Par 2/genética , Fisura del Paladar/genética , Fisura del Paladar/fisiopatología , Codón sin Sentido/genética , Anomalías Craneofaciales/fisiopatología , Exoma/genética , Femenino , Mutación del Sistema de Lectura/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Discapacidad Intelectual/fisiopatología , Trastornos del Desarrollo del Lenguaje/fisiopatología , MasculinoRESUMEN
This study investigated the effects of continuous moderate-intensity exercise (MIE) and high-intensity interval exercise (HIIE) in combination with short exposure to hypoxia on appetite and plasma concentrations of acylated ghrelin, peptide YY (PYY), and glucagon-like peptide-1 (GLP-1). Twelve healthy males completed four, 2.6 h trials in a random order: (1) MIE-normoxia, (2) MIE-hypoxia, (3) HIIE-normoxia, and (4) HIIE-hypoxia. Exercise took place in an environmental chamber. During MIE, participants ran for 50 min at 70% of altitude-specific maximal oxygen uptake (VËO2max) and during HIIE performed 6 × 3 min running at 90% VËO2max interspersed with 6 × 3 min active recovery at 50% VËO2max with a 7 min warm-up and cool-down at 70% VËO2max (50 min total). In hypoxic trials, exercise was performed at a simulated altitude of 2980 m (14.5% O2). Exercise was completed after a standardised breakfast. A second meal standardised to 30% of participants' daily energy requirements was provided 45 min after exercise. Appetite was suppressed more in hypoxia than normoxia during exercise, post-exercise, and for the full 2.6 h trial period (linear mixed modelling, p <0.05). Plasma acylated ghrelin concentrations were lower in hypoxia than normoxia post-exercise and for the full 2.6 h trial period (p <0.05). PYY concentrations were higher in HIIE than MIE under hypoxic conditions during exercise (p = 0.042). No differences in GLP-1 were observed between conditions (p > 0.05). These findings demonstrate that short exposure to hypoxia causes suppressions in appetite and plasma acylated ghrelin concentrations. Furthermore, appetite responses to exercise do not appear to be influenced by exercise modality.