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1.
J Med Ethics ; 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32978304

RESUMO

COVID-19 poses an exceptional threat to global public health and well-being. Recognition of the need to develop effective vaccines at unprecedented speed has led to calls to accelerate research pathways ethically, including by conducting challenge studies (also known as controlled human infection studies (CHIs)) with SARS-CoV-2 (the virus which causes COVID-19). Such research is controversial, with concerns being raised about the social, legal, ethical and clinical implications of infecting healthy volunteers with SARS-CoV-2 for research purposes. Systematic risk evaluations are critical to inform assessments of the ethics of any proposed SARS-CoV-2 CHIs. Such evaluations will necessarily take place within a rapidly changing and at times contested epidemiological landscape, in which differing criteria for the ethical acceptability of research risks have been proposed. This paper critically reviews two such criteria and evaluates whether the use of effective treatment should be a necessary condition for the ethical acceptability of SARS-CoV-2 CHIs, and whether the choice of study sites should be influenced by COVID-19 incidence levels. The paper concludes that ethical evaluations of proposed SARS-CoV-2 CHIs should be informed by rigorous, consultative and holistic approaches to systematic risk assessment.

2.
J Med Ethics ; 2020 May 04.
Artigo em Inglês | MEDLINE | ID: covidwho-197424

RESUMO

In this paper we discuss ethical implications of the use of mobile phone apps in the control of the COVID-19 pandemic. Contact tracing is a well-established feature of public health practice during infectious disease outbreaks and epidemics. However, the high proportion of pre-symptomatic transmission in COVID-19 means that standard contact tracing methods are too slow to stop the progression of infection through the population. To address this problem, many countries around the world have deployed or are developing mobile phone apps capable of supporting instantaneous contact tracing. Informed by the on-going mapping of 'proximity events' these apps are intended both to inform public health policy and to provide alerts to individuals who have been in contact with a person with the infection. The proposed use of mobile phone data for 'intelligent physical distancing' in such contexts raises a number of important ethical questions. In our paper, we outline some ethical considerations that need to be addressed in any deployment of this kind of approach as part of a multidimensional public health response. We also, briefly, explore the implications for its use in future infectious disease outbreaks.

3.
J Med Ethics ; 2020 May 04.
Artigo em Inglês | MEDLINE | ID: covidwho-214131

RESUMO

In this paper we discuss ethical implications of the use of mobile phone apps in the control of the COVID-19 pandemic. Contact tracing is a well-established feature of public health practice during infectious disease outbreaks and epidemics. However, the high proportion of pre-symptomatic transmission in COVID-19 means that standard contact tracing methods are too slow to stop the progression of infection through the population. To address this problem, many countries around the world have deployed or are developing mobile phone apps capable of supporting instantaneous contact tracing. Informed by the on-going mapping of 'proximity events' these apps are intended both to inform public health policy and to provide alerts to individuals who have been in contact with a person with the infection. The proposed use of mobile phone data for 'intelligent physical distancing' in such contexts raises a number of important ethical questions. In our paper, we outline some ethical considerations that need to be addressed in any deployment of this kind of approach as part of a multidimensional public health response. We also, briefly, explore the implications for its use in future infectious disease outbreaks.

4.
J Med Ethics ; 46(7): 427-431, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32366705

RESUMO

In this paper we discuss ethical implications of the use of mobile phone apps in the control of the COVID-19 pandemic. Contact tracing is a well-established feature of public health practice during infectious disease outbreaks and epidemics. However, the high proportion of pre-symptomatic transmission in COVID-19 means that standard contact tracing methods are too slow to stop the progression of infection through the population. To address this problem, many countries around the world have deployed or are developing mobile phone apps capable of supporting instantaneous contact tracing. Informed by the on-going mapping of 'proximity events' these apps are intended both to inform public health policy and to provide alerts to individuals who have been in contact with a person with the infection. The proposed use of mobile phone data for 'intelligent physical distancing' in such contexts raises a number of important ethical questions. In our paper, we outline some ethical considerations that need to be addressed in any deployment of this kind of approach as part of a multidimensional public health response. We also, briefly, explore the implications for its use in future infectious disease outbreaks.


Assuntos
Telefone Celular , Busca de Comunicante/ética , Busca de Comunicante/métodos , Infecções por Coronavirus/epidemiologia , Pneumonia Viral/epidemiologia , Betacoronavirus , Temas Bioéticos , Controle de Doenças Transmissíveis/métodos , Liberdade , Humanos , Aplicativos Móveis , Pandemias , Privacidade , Confiança
5.
Artigo em Inglês | MEDLINE | ID: mdl-32319732

RESUMO

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.

6.
Hum Mutat ; 41(5): 1042-1050, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32097528

RESUMO

Pathogenic variants in ZMYND11, which acts as a transcriptional repressor, have been associated with intellectual disability, behavioral abnormalities, and seizures. Only 11 affected individuals have been reported to date, and the phenotype associated with pathogenic variants in this gene have not been fully defined. Here, we present 16 additional patients with predicted pathogenic heterozygous variants in including four individuals from the same family, to further delineate and expand the genotypic and phenotypic spectrum of ZMYND11-related syndromic intellectual disability. The associated phenotype includes developmental delay, particularly affecting speech, mild-moderate intellectual disability, significant behavioral abnormalities, seizures, and hypotonia. There are subtle shared dysmorphic features, including prominent eyelashes and eyebrows, a depressed nasal bridge with bulbous nasal tip, anteverted nares, thin vermilion of the upper lip, and wide mouth. Novel features include brachydactyly and tooth enamel hypoplasia. Most identified variants are likely to result in premature truncation and/or nonsense-mediated decay. Two ZMYND11 variants located in the final exon-p.(Gln586*) (likely escaping nonsense-mediated decay) and p.(Cys574Arg)-are predicted to disrupt the MYND-type zinc-finger motif and likely interfere with binding to its interaction partners. Hence, the homogeneous phenotype likely results from a common mechanism of loss-of-function.

7.
Am J Hum Genet ; 106(3): 405-411, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32109420

RESUMO

Recurrent somatic variants in SPOP are cancer specific; endometrial and prostate cancers result from gain-of-function and dominant-negative effects toward BET proteins, respectively. By using clinical exome sequencing, we identified six de novo pathogenic missense variants in SPOP in seven individuals with developmental delay and/or intellectual disability, facial dysmorphisms, and congenital anomalies. Two individuals shared craniofacial dysmorphisms, including congenital microcephaly, that were strikingly different from those of the other five individuals, who had (relative) macrocephaly and hypertelorism. We measured the effect of SPOP variants on BET protein amounts in human Ishikawa endometrial cancer cells and patient-derived cell lines because we hypothesized that variants would lead to functional divergent effects on BET proteins. The de novo variants c.362G>A (p.Arg121Gln) and c. 430G>A (p.Asp144Asn), identified in the first two individuals, resulted in a gain of function, and conversely, the c.73A>G (p.Thr25Ala), c.248A>G (p.Tyr83Cys), c.395G>T (p.Gly132Val), and c.412C>T (p.Arg138Cys) variants resulted in a dominant-negative effect. Our findings suggest that these opposite functional effects caused by the variants in SPOP result in two distinct and clinically recognizable syndromic forms of intellectual disability with contrasting craniofacial dysmorphisms.


Assuntos
Mutação de Sentido Incorreto , Transtornos do Neurodesenvolvimento/genética , Proteínas Nucleares/genética , Proteínas Repressoras/genética , Adolescente , Criança , Pré-Escolar , Facies , Feminino , Humanos , Lactente , Deficiência Intelectual/genética , Masculino , Crânio/anormalidades , Adulto Jovem
8.
Genet Med ; 22(2): 389-397, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31388190

RESUMO

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.

10.
Am J Med Genet C Semin Med Genet ; 181(4): 557-564, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31721432

RESUMO

CHD8 has been reported as an autism susceptibility/intellectual disability gene but emerging evidence suggests that it additionally causes an overgrowth phenotype. This study reports 27 unrelated patients with pathogenic or likely pathogenic CHD8 variants (25 null variants, two missense variants) and a male:female ratio of 21:6 (3.5:1, p < .01). All patients presented with intellectual disability, with 85% in the mild or moderate range, and 85% had a height and/or head circumference ≥2 standard deviations above the mean, meeting our clinical criteria for overgrowth. Behavioral problems were reported in the majority of patients (78%), with over half (56%) either formally diagnosed with an autistic spectrum disorder or described as having autistic traits. Additional clinical features included neonatal hypotonia (33%), and less frequently seizures, pes planus, scoliosis, fifth finger clinodactyly, umbilical hernia, and glabellar hemangioma (≤15% each). These results suggest that, in addition to its established link with autism and intellectual disability, CHD8 causes an overgrowth phenotype, and should be considered in the differential diagnosis of patients presenting with increased height and/or head circumference in association with intellectual disability.


Assuntos
Caderinas/genética , Transtornos do Crescimento/genética , Fenótipo , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Deficiência Intelectual/genética , Masculino , Síndrome , Adulto Jovem
11.
Am J Hum Genet ; 105(5): 933-946, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31607427

RESUMO

Trio-based whole-exome sequence (WES) data have established confident genetic diagnoses in ∼40% of previously undiagnosed individuals recruited to the Deciphering Developmental Disorders (DDD) study. Here we aim to use the breadth of phenotypic information recorded in DDD to augment diagnosis and disease variant discovery in probands. Median Euclidean distances (mEuD) were employed as a simple measure of similarity of quantitative phenotypic data within sets of ≥10 individuals with plausibly causative de novo mutations (DNM) in 28 different developmental disorder genes. 13/28 (46.4%) showed significant similarity for growth or developmental milestone metrics, 10/28 (35.7%) showed similarity in HPO term usage, and 12/28 (43%) showed no phenotypic similarity. Pairwise comparisons of individuals with high-impact inherited variants to the 32 individuals with causative DNM in ANKRD11 using only growth z-scores highlighted 5 likely causative inherited variants and two unrecognized DNM resulting in an 18% diagnostic uplift for this gene. Using an independent approach, naive Bayes classification of growth and developmental data produced reasonably discriminative models for the 24 DNM genes with sufficiently complete data. An unsupervised naive Bayes classification of 6,993 probands with WES data and sufficient phenotypic information defined 23 in silico syndromes (ISSs) and was used to test a "phenotype first" approach to the discovery of causative genotypes using WES variants strictly filtered on allele frequency, mutation consequence, and evidence of constraint in humans. This highlighted heterozygous de novo nonsynonymous variants in SPTBN2 as causative in three DDD probands.


Assuntos
Deficiências do Desenvolvimento/genética , Teorema de Bayes , Criança , Nanismo/genética , Exoma/genética , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Heterozigoto , Humanos , Masculino , Mutação/genética , Fenótipo , Proteínas Repressoras/genética , Espectrina/genética , Sequenciamento Completo do Exoma
12.
Trials ; 20(1): 463, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31358032

RESUMO

BACKGROUND: Differentiating infection from inflammation in acute pancreatitis is difficult, leading to overuse of antibiotics. Procalcitonin (PCT) measurement is a means of distinguishing infection from inflammation as levels rise rapidly in response to a pro-inflammatory stimulus of bacterial origin and normally fall after successful treatment. Algorithms based on PCT measurement can differentiate bacterial sepsis from a systemic inflammatory response. The PROCalcitonin-based algorithm for antibiotic use in Acute Pancreatitis (PROCAP) trial tests the hypothesis that a PCT-based algorithm to guide initiation, continuation and discontinuation of antibiotics will lead to reduced antibiotic use in patients with acute pancreatitis and without an adverse effect on outcome. METHODS: This is a single-centre, randomised, controlled, single-blind, two-arm pragmatic clinical and cost-effectiveness trial. Patients with a clinical diagnosis of acute pancreatitis will be allocated on a 1:1 basis to intervention or standard care. Intervention will involve the use of a PCT-based algorithm to guide antibiotic use. The primary outcome measure will be the binary outcome of antibiotic use during index admission. Secondary outcome measures include: safety non-inferiority endpoint all-cause mortality; days of antibiotic use; clinical infections; new isolates of multiresistant bacteria; duration of inpatient stay; episode-related mortality and cause; quality of life (EuroQol EQ-5D); and cost analysis. A 20% absolute change in antibiotic use would be a clinically important difference. A study with 80% power and 5% significance (two-sided) would require 97 patients in each arm (194 patients in total): the study will aim to recruit 200 patients. Analysis will follow intention-to-treat principles. DISCUSSION: When complete, PROCAP will be the largest randomised trial of the use of a PCT algorithm to guide initiation, continuation and cessation of antibiotics in acute pancreatitis. PROCAP is the only randomised trial to date to compare standard care of acute pancreatitis as defined by the International Association of Pancreatology/American Pancreatic Association guidelines to patients having standard care but with all antibiotic prescribing decisions based on PCT measurement. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number, ISRCTN50584992. Registered on 7 February 2018.


Assuntos
Algoritmos , Antibacterianos/uso terapêutico , Técnicas de Apoio para a Decisão , Monitoramento de Medicamentos/métodos , Pancreatite/tratamento farmacológico , Pró-Calcitonina/sangue , Antibacterianos/efeitos adversos , Antibacterianos/economia , Biomarcadores/sangue , Tomada de Decisão Clínica , Ensaios Clínicos Fase III como Assunto , Redução de Custos , Análise Custo-Benefício , Custos de Medicamentos , Monitoramento de Medicamentos/economia , Inglaterra , Humanos , Pancreatite/sangue , Pancreatite/diagnóstico , Pancreatite/economia , Ensaios Clínicos Pragmáticos como Assunto , Valor Preditivo dos Testes , Método Simples-Cego , Fatores de Tempo , Resultado do Tratamento
14.
Genet Med ; 21(9): 2059-2069, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30923367

RESUMO

PURPOSE: To investigate the effect of different DEAF1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and on DEAF1 activity in vitro. METHODS: We assembled a cohort of 23 patients with de novo and biallelic DEAF1 variants, described the genotype-phenotype correlation, and investigated the differential effect of de novo and recessive variants on transcription assays using DEAF1 and Eif4g3 promoter luciferase constructs. RESULTS: The proportion of the most prevalent phenotypic features, including intellectual disability, speech delay, motor delay, autism, sleep disturbances, and a high pain threshold, were not significantly different in patients with biallelic and pathogenic de novo DEAF1 variants. However, microcephaly was exclusively observed in patients with recessive variants (p < 0.0001). CONCLUSION: We propose that different variants in the DEAF1 gene result in a phenotypic spectrum centered around neurodevelopmental delay. While a pathogenic de novo dominant variant would also incapacitate the product of the wild-type allele and result in a dominant-negative effect, a combination of two recessive variants would result in a partial loss of function. Because the clinical picture can be nonspecific, detailed phenotype information, segregation, and functional analysis are fundamental to determine the pathogenicity of novel variants and to improve the care of these patients.


Assuntos
Proteínas de Ligação a DNA/genética , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Microcefalia/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Alelos , Transtorno Autístico/genética , Transtorno Autístico/patologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/patologia , Exoma/genética , Feminino , Estudos de Associação Genética , Humanos , Deficiência Intelectual/patologia , Transtornos do Desenvolvimento da Linguagem/genética , Transtornos do Desenvolvimento da Linguagem/patologia , Masculino , Microcefalia/patologia , Mutação de Sentido Incorreto/genética , Adulto Jovem
15.
Am J Med Genet A ; 179(3): 344-349, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30637921

RESUMO

Primrose syndrome is a rare autosomal dominant condition caused by heterozygous missense variants within ZBTB20. Through an exome sequencing approach (as part of the Deciphering Developmental Disorders [DDD] study) we have identified five unrelated individuals with previously unreported, de novo ZBTB20 pathogenic missense variants. All five missense variants targeted the C2H2 zinc finger domains. This genotype-up approach has allowed further refinement of the Primrose syndrome phenotype. Major characteristics (>90% individuals) include an intellectual disability (most frequently in the moderate range), a recognizable facial appearance and brain MRI abnormalities, particularly abnormalities of the corpus callosum. Other frequent clinical associations (in 50-90% individuals) include sensorineural hearing loss (83%), hypotonia (78%), cryptorchidism in males (75%), macrocephaly (72%), behavioral issues (56%), and dysplastic/hypoplastic nails (57%). Based upon these clinical data we discuss our current management of patients with Primrose syndrome.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Calcinose/diagnóstico , Calcinose/genética , Otopatias/diagnóstico , Otopatias/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Atrofia Muscular/diagnóstico , Atrofia Muscular/genética , Proteínas do Tecido Nervoso/genética , Fenótipo , Fatores de Transcrição/genética , Criança , Pré-Escolar , Facies , Feminino , Loci Gênicos , Genótipo , Humanos , Imagem por Ressonância Magnética , Masculino , Mutação
17.
Science ; 362(6419): 1161-1164, 2018 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-30409806

RESUMO

We estimated the genome-wide contribution of recessive coding variation in 6040 families from the Deciphering Developmental Disorders study. The proportion of cases attributable to recessive coding variants was 3.6% in patients of European ancestry, compared with 50% explained by de novo coding mutations. It was higher (31%) in patients with Pakistani ancestry, owing to elevated autozygosity. Half of this recessive burden is attributable to known genes. We identified two genes not previously associated with recessive developmental disorders, KDM5B and EIF3F, and functionally validated them with mouse and cellular models. Our results suggest that recessive coding variants account for a small fraction of currently undiagnosed nonconsanguineous individuals, and that the role of noncoding variants, incomplete penetrance, and polygenic mechanisms need further exploration.


Assuntos
Deficiências do Desenvolvimento/genética , Genes Recessivos , Código Genético , Variação Genética , Penetrância , Animais , Modelos Animais de Doenças , Fator de Iniciação 3 em Eucariotos/genética , Europa (Continente) , Estudo de Associação Genômica Ampla , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Camundongos , Proteínas Nucleares/genética , Paquistão , Filogenia , Proteínas Repressoras/genética
18.
Ann Neurol ; 84(5): 766-780, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30295347

RESUMO

OBJECTIVE: Several small case series identified KCTD7 mutations in patients with a rare autosomal recessive disorder designated progressive myoclonic epilepsy (EPM3) and neuronal ceroid lipofuscinosis (CLN14). Despite the name KCTD (potassium channel tetramerization domain), KCTD protein family members lack predicted channel domains. We sought to translate insight gained from yeast studies to uncover disease mechanisms associated with deficiencies in KCTD7 of unknown function. METHODS: Novel KCTD7 variants in new and published patients were assessed for disease causality using genetic analyses, cell-based functional assays of patient fibroblasts and knockout yeast, and electron microscopy of patient samples. RESULTS: Patients with KCTD7 mutations can exhibit movement disorders or developmental regression before seizure onset, and are distinguished from similar disorders by an earlier age of onset. Although most published KCTD7 patient variants were excluded from a genome sequence database of normal human variations, most newly identified patient variants are present in this database, potentially challenging disease causality. However, genetic analysis and impaired biochemical interactions with cullin 3 support a causal role for patient KCTD7 variants, suggesting deleterious alleles of KCTD7 and other rare disease variants may be underestimated. Both patient-derived fibroblasts and yeast lacking Whi2 with sequence similarity to KCTD7 have impaired autophagy consistent with brain pathology. INTERPRETATION: Biallelic KCTD7 mutations define a neurodegenerative disorder with lipofuscin and lipid droplet accumulation but without defining features of neuronal ceroid lipofuscinosis or lysosomal storage disorders. KCTD7 deficiency appears to cause an underlying autophagy-lysosome defect conserved in yeast, thereby assigning a biological role for KCTD7. Ann Neurol 2018;84:774-788.


Assuntos
Autofagia/genética , Lisossomos/genética , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Canais de Potássio/deficiência , Idade de Início , Pré-Escolar , Feminino , Humanos , Lactente , Lisossomos/patologia , Masculino , Mutação , Linhagem , Canais de Potássio/genética , Proteínas de Saccharomyces cerevisiae/genética
19.
Am J Med Genet B Neuropsychiatr Genet ; 177(4): 397-405, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29603867

RESUMO

Recurrent deletions and duplications at the 2q13 locus have been associated with developmental delay (DD) and dysmorphisms. We aimed to undertake detailed clinical characterization of individuals with 2q13 copy number variations (CNVs), with a focus on behavioral and psychiatric phenotypes. Participants were recruited via the Unique chromosomal disorder support group, U.K. National Health Service Regional Genetics Centres, and the DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources (DECIPHER) database. A review of published 2q13 patient case reports was undertaken to enable combined phenotypic analysis. We present a new case series of 2q13 CNV carriers (21 deletion, 4 duplication) and the largest ever combined analysis with data from published studies, making a total of 54 deletion and 23 duplication carriers. DD/intellectual disabilities was identified in the majority of carriers (79% deletion, 70% duplication), although in the new cases 52% had an IQ in the borderline or normal range. Despite the median age of the new cases being only 9 years, 64% had a clinical psychiatric diagnosis. Combined analysis found attention deficit hyperactivity disorder (ADHD) to be the most frequent diagnosis (48% deletion, 60% duplication), followed by autism spectrum disorders (33% deletion, 17% duplication). Aggressive (33%) and self-injurious behaviors (33%) were also identified in the new cases. CNVs at 2q13 are typically associated with DD with mildly impaired intelligence, and a high rate of childhood psychiatric diagnoses-particularly ADHD. We have further characterized the clinical phenotype related to imbalances of the 2q13 region and identified it as a region of interest for the neurobiological investigation of ADHD.


Assuntos
Cromossomos Humanos Par 2/genética , Deficiências do Desenvolvimento/genética , Transtornos Mentais/genética , Adolescente , Adulto , Criança , Pré-Escolar , Aberrações Cromossômicas , Deleção Cromossômica , Duplicação Cromossômica , Variações do Número de Cópias de DNA/genética , Feminino , Duplicação Gênica/genética , Humanos , Deficiência Intelectual/genética , Masculino , Fenótipo , Reino Unido
20.
Am J Hum Genet ; 102(5): 985-994, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29656860

RESUMO

N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal Mendelian disorder involving a c.109T>C (p.Ser37Pro) missense variant in NAA10, which encodes the catalytic subunit of the N-terminal acetyltransferase A (NatA) complex. The auxiliary subunit of the NatA complex, NAA15, is the dimeric binding partner for NAA10. Through a genotype-first approach with whole-exome or genome sequencing (WES/WGS) and targeted sequencing analysis, we identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants in NAA15. Clinical features of affected individuals with LGD variants in NAA15 include variable levels of intellectual disability, delayed speech and motor milestones, and autism spectrum disorder. Additionally, mild craniofacial dysmorphology, congenital cardiac anomalies, and seizures are present in some subjects. RNA analysis in cell lines from two individuals showed degradation of the transcripts with LGD variants, probably as a result of nonsense-mediated decay. Functional assays in yeast confirmed a deleterious effect for two of the LGD variants in NAA15. Further supporting a mechanism of haploinsufficiency, individuals with copy-number variant (CNV) deletions involving NAA15 and surrounding genes can present with mild intellectual disability, mild dysmorphic features, motor delays, and decreased growth. We propose that defects in NatA-mediated N-terminal acetylation (NTA) lead to variable levels of neurodevelopmental disorders in humans, supporting the importance of the NatA complex in normal human development.


Assuntos
Anormalidades Múltiplas/genética , Transtorno do Espectro Autista/genética , Predisposição Genética para Doença , Variação Genética , Deficiência Intelectual/genética , Acetiltransferase N-Terminal A/genética , Acetiltransferase N-Terminal E/genética , Adolescente , Adulto , Linhagem Celular , Criança , Éxons/genética , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Acetiltransferase N-Terminal A/metabolismo , Acetiltransferase N-Terminal E/metabolismo , Linhagem , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Saccharomyces cerevisiae/metabolismo
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