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Objectives: Purine-rich element-binding protein alpha (PURA) regulates gene expression and is ubiquitously expressed with an enrichment in neural tissues. Pathogenic variants in PURA cause the neurodevelopmental disorder PURA syndrome that has a variable phenotype but typically comprises moderate-to-severe global developmental delay, intellectual disability, early-onset hypotonia and hypothermia, epilepsy, feeding difficulties, movement disorders, and subtle facial dysmorphism. Speech is reportedly absent in most, but the specific linguistic phenotype is not well described. Methods: We used genome sequencing to identify a pathogenic gene variant as part of a study of children ascertained for severe primary speech disorder in the absence of moderate or severe ID. Results: The novel PURA c.296G>T (p.Arg99Leu) pathogenic missense variant segregated in the female proband and her affected mother. The proband had dysarthria; phonological disorder; and severe receptive and expressive language impairment, borderline intellect, attention difficulties, oropharyngeal dysmotility, and dysmorphic facial features. Her mother had dysarthria, moderate receptive language impairment, and borderline intellect. Both the proband and her mother completed mainstream schooling with classroom support. Discussion: This is the first inherited PURA pathogenic germline variant in over 600 unrelated families documented on ClinVar or reported in the literature. PURA testing should be considered in families with primary speech disorder and borderline intellectual disability, given the specific genetic counseling implications.
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Oculopharyngodistal myopathy (OPDM) is an inherited myopathy manifesting with ptosis, dysphagia and distal weakness. Pathologically it is characterised by rimmed vacuoles and intranuclear inclusions on muscle biopsy. In recent years CGG ⢠CCG repeat expansion in four different genes were identified in OPDM individuals in Asian populations. None of these have been found in affected individuals of non-Asian ancestry. In this study we describe the identification of CCG expansions in ABCD3, ranging from 118 to 694 repeats, in 35 affected individuals across eight unrelated OPDM families of European ancestry. ABCD3 transcript appears upregulated in fibroblasts and skeletal muscle from OPDM individuals, suggesting a potential role of over-expression of CCG repeat containing ABCD3 transcript in progressive skeletal muscle degeneration. The study provides further evidence of the role of non-coding repeat expansions in unsolved neuromuscular diseases and strengthens the association between the CGG ⢠CCG repeat motif and a specific pattern of muscle weakness.
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Músculo Esquelético , Expansión de Repetición de Trinucleótido , Población Blanca , Humanos , Masculino , Femenino , Adulto , Expansión de Repetición de Trinucleótido/genética , Persona de Mediana Edad , Población Blanca/genética , Músculo Esquelético/patología , Transportadoras de Casetes de Unión a ATP/genética , Miopatías Estructurales Congénitas/genética , Miopatías Estructurales Congénitas/patología , Linaje , Anciano , Adulto Joven , Fibroblastos/metabolismo , Fibroblastos/patología , Debilidad Muscular/genética , Debilidad Muscular/patología , Adolescente , Distrofias MuscularesRESUMEN
The application of genomics has greatly increased the diagnosis of specific monogenic causes of intellectual disability and improved our understanding of the neuronal processes that result in cognitive impairment. Meanwhile, families are building rare disease communities and seeking disease-specific treatments to change the trajectory of health and developmental outcomes for their children. To date, treatments for intellectual disability have focussed on metabolic disorders, where early treatment has improved cognition and neurodevelopmental outcomes. In this article, we discuss the treatment strategies that may be possible to change the neurodevelopmental outcome in a broader range of genetic forms of intellectual disability. These strategies include substrate modification, enzyme replacement therapy, gene therapy and molecular therapies. We argue that intellectual disability should now be considered a potentially treatable condition and a strong candidate for precision medicine.
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Discapacidad Intelectual , Humanos , Discapacidad Intelectual/terapia , Discapacidad Intelectual/diagnóstico , Terapia Genética , Niño , Terapia de Reemplazo EnzimáticoRESUMEN
Observational studies have a critical role in disability research, providing the opportunity to address a range of research questions. Over the past decades, there have been substantial shifts and developments in statistical methods for observational studies, most notably for causal inference. In this review, we provide an overview of modern design and analysis concepts critical for observational studies, drawing examples from the field of disability research and highlighting the challenges in this field, to inform the readership on important statistical considerations for their studies.
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INTRODUCTION: Newborn bloodspot screening (NBS) is a highly successful public health programme that uses biochemical and other assays to screen for severe but treatable childhood-onset conditions. Introducing genomic sequencing into NBS programmes increases the range of detectable conditions but raises practical and ethical issues. Evidence from prospectively ascertained cohorts is required to guide policy and future implementation. This study aims to develop, implement and evaluate a genomic NBS (gNBS) pilot programme. METHODS AND ANALYSIS: The BabyScreen+ study will pilot gNBS in three phases. In the preimplementation phase, study materials, including education resources, decision support and data collection tools, will be designed. Focus groups and key informant interviews will also be undertaken to inform delivery of the study and future gNBS programmes. During the implementation phase, we will prospectively recruit birth parents in Victoria, Australia, to screen 1000 newborns for over 600 severe, treatable, childhood-onset conditions. Clinically accredited whole genome sequencing will be performed following standard NBS using the same sample. High chance results will be returned by genetic healthcare professionals, with follow-on genetic and other confirmatory testing and referral to specialist services as required. The postimplementation phase will evaluate the feasibility of gNBS as the primary aim, and assess ethical, implementation, psychosocial and health economic factors to inform future service delivery. ETHICS AND DISSEMINATION: This project received ethics approval from the Royal Children's Hospital Melbourne Research Ethics Committee: HREC/91500/RCHM-2023, HREC/90929/RCHM-2022 and HREC/91392/RCHM-2022. Findings will be disseminated to policy-makers, and through peer-reviewed journals and conferences.
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Genómica , Tamizaje Neonatal , Niño , Humanos , Recién Nacido , Proyectos Piloto , Estudios Prospectivos , VictoriaRESUMEN
This study aimed to determine the diagnostic yield of singleton exome sequencing and subsequent research-based trio exome analysis in children with a spectrum of brain malformations seen commonly in clinical practice. We recruited children ≤ 18 years old with a brain malformation diagnosed by magnetic resonance imaging and consistent with an established list of known genetic causes. Patients were ascertained nationally from eight tertiary paediatric centres as part of the Australian Genomics Brain Malformation Flagship. Chromosome microarray was required for all children, and those with pathogenic copy number changes were excluded. Cytomegalovirus polymerase chain reaction on neonatal blood spots was performed on all children with polymicrogyria with positive patients excluded. Singleton exome sequencing was performed through a diagnostic laboratory and analysed using a clinical exome sequencing pipeline. Undiagnosed patients were followed up in a research setting, including reanalysis of the singleton exome data and subsequent trio exome sequencing. A total of 102 children were recruited. Ten malformation subtypes were identified with the commonest being polymicrogyria (36%), pontocerebellar hypoplasia (14%), periventricular nodular heterotopia (11%), tubulinopathy (10%), lissencephaly (10%) and cortical dysplasia (9%). The overall diagnostic yield for the clinical singleton exome sequencing was 36%, which increased to 43% after research follow-up. The main source of increased diagnostic yield was the reanalysis of the singleton exome data to include newly discovered gene-disease associations. One additional diagnosis was made by trio exome sequencing. The highest phenotype-based diagnostic yields were for cobblestone malformation, tubulinopathy and lissencephaly and the lowest for cortical dysplasia and polymicrogyria. Pathogenic variants were identified in 32 genes, with variants in 6/32 genes occurring in more than one patient. The most frequent genetic diagnosis was pathogenic variants in TUBA1A. This study shows that over 40% of patients with common brain malformations have a genetic aetiology identified by exome sequencing. Periodic reanalysis of exome data to include newly identified genes was of greater value in increasing diagnostic yield than the expansion to trio exome. This study highlights the genetic and phenotypic heterogeneity of brain malformations, the importance of a multidisciplinary approach to diagnosis and the large number of patients that remain without a genetic diagnosis despite clinical exome sequencing and research reanalysis.
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The Mendelian disorders of chromatin machinery (MDCMs) represent a distinct subgroup of disorders that present with neurodevelopmental disability. The chromatin machinery regulates gene expression by a range of mechanisms, including by post-translational modification of histones, responding to histone marks, and remodelling nucleosomes. Some of the MDCMs that impact on histone modification may have potential therapeutic interventions. Two potential treatment strategies are to enhance the intracellular pool of metabolites that can act as substrates for histone modifiers and the use of medications that may inhibit or promote the modification of histone residues to influence gene expression. In this article we discuss the influence and potential treatments of histone modifications involving histone acetylation and histone methylation. Genomic technologies are facilitating earlier diagnosis of many Mendelian disorders, providing potential opportunities for early treatment from infancy. This has parallels with how inborn errors of metabolism have been afforded early treatment with newborn screening. Before this promise can be fulfilled, we require greater understanding of the biochemical fingerprint of these conditions, which may provide opportunities to supplement metabolites that can act as substrates for chromatin modifying enzymes. Importantly, understanding the metabolomic profile of affected individuals may also provide disorder-specific biomarkers that will be critical for demonstrating efficacy of treatment, as treatment response may not be able to be accurately assessed by clinical measures.
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Cromatina , Redes y Vías Metabólicas , Humanos , Cromatina/genética , Cromatina/metabolismo , Redes y Vías Metabólicas/genética , Histonas/metabolismo , Histonas/genética , Procesamiento Proteico-Postraduccional , Acetilación , Errores Innatos del Metabolismo/genética , Errores Innatos del Metabolismo/terapia , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/metabolismo , Ensamble y Desensamble de Cromatina/genética , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/terapia , Enfermedades Genéticas Congénitas/metabolismo , Recién Nacido , MetilaciónRESUMEN
Pathogenic variants in multiple genes on the X chromosome have been implicated in syndromic and non-syndromic intellectual disability disorders. ZFX on Xp22.11 encodes a transcription factor that has been linked to diverse processes including oncogenesis and development, but germline variants have not been characterized in association with disease. Here, we present clinical and molecular characterization of 18 individuals with germline ZFX variants. Exome or genome sequencing revealed 11 variants in 18 subjects (14 males and 4 females) from 16 unrelated families. Four missense variants were identified in 11 subjects, with seven truncation variants in the remaining individuals. Clinical findings included developmental delay/intellectual disability, behavioral abnormalities, hypotonia, and congenital anomalies. Overlapping and recurrent facial features were identified in all subjects, including thickening and medial broadening of eyebrows, variations in the shape of the face, external eye abnormalities, smooth and/or long philtrum, and ear abnormalities. Hyperparathyroidism was found in four families with missense variants, and enrichment of different tumor types was observed. In molecular studies, DNA-binding domain variants elicited differential expression of a small set of target genes relative to wild-type ZFX in cultured cells, suggesting a gain or loss of transcriptional activity. Additionally, a zebrafish model of ZFX loss displayed an altered behavioral phenotype, providing additional evidence for the functional significance of ZFX. Our clinical and experimental data support that variants in ZFX are associated with an X-linked intellectual disability syndrome characterized by a recurrent facial gestalt, neurocognitive and behavioral abnormalities, and an increased risk for congenital anomalies and hyperparathyroidism.
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Hiperparatiroidismo , Discapacidad Intelectual , Trastornos del Neurodesarrollo , Masculino , Femenino , Animales , Humanos , Discapacidad Intelectual/patología , Pez Cebra/genética , Mutación Missense/genética , Factores de Transcripción/genética , Fenotipo , Trastornos del Neurodesarrollo/genéticaRESUMEN
Pathogenic variants in DDX3X are associated with neurodevelopmental disorders. Communication impairments are commonly reported, yet specific speech and language diagnoses have not been delineated, preventing prognostic counseling and targeted therapies. Here, we characterized speech and language in 38 female individuals, aged 1.69-24.34 years, with pathogenic and likely pathogenic DDX3X variants (missense, n = 13; nonsense, n = 12; frameshift, n = 7; splice site, n = 3; synonymous, n = 2; deletion, n = 1). Standardized speech, language, motor, social, and adaptive behavior assessments were administered. All participants had gross motor deficits in infancy (34/34), and fine motor deficits were common throughout childhood (94%; 32/34). Intellectual disability was reported in 86% (24/28) of participants over 4 years of age. Expressive, receptive, and social communication skills were, on average, severely impaired. However, receptive language was significantly stronger than expressive language ability. Over half of the assessed participants were minimally verbal (66%; 22/33; range = 2 years 2 months-24 years 4 months; mean = 8 years; SD = 6 years) and augmented speech with sign language, gestures, or digital devices. A quarter of the cohort had childhood apraxia of speech (25%; 9/36). Despite speech and language impairments, social motivation was a relevant strength. Many participants used augmentative and alternative communication (AAC), underscoring the need for early, tailored, and comprehensive AAC intervention.
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ARN Helicasas DEAD-box , Trastornos del Neurodesarrollo , Habla , Humanos , Femenino , Preescolar , Niño , Adolescente , Trastornos del Neurodesarrollo/genética , Lactante , Adulto Joven , ARN Helicasas DEAD-box/genética , Habla/fisiología , Discapacidad Intelectual/genética , Adulto , Masculino , Lenguaje , Trastornos del Habla , Comunicación , Trastornos del Desarrollo del Lenguaje/genéticaRESUMEN
The disconnected (disco)-interacting protein 2 (DIP2) gene was first identified in D. melanogaster and contains a DNA methyltransferase-associated protein 1 (DMAP1) binding domain, Acyl-CoA synthetase domain and AMP-binding sites. DIP2 regulates axonal bifurcation of the mushroom body neurons in D. melanogaster and is required for axonal regeneration in the neurons of C. elegans. The DIP2 homologues in vertebrates, Disco-interacting protein 2 homolog A (DIP2A), Disco-interacting protein 2 homolog B (DIP2B), and Disco-interacting protein 2 homolog C (DIP2C), are highly conserved and expressed widely in the central nervous system. Although there is evidence that DIP2C plays a role in cognition, reports of pathogenic variants in these genes are rare and their significance is uncertain. We present 23 individuals with heterozygous DIP2C variants, all manifesting developmental delays that primarily affect expressive language and speech articulation. Eight patients had de novo variants predicting loss-of-function in the DIP2C gene, two patients had de novo missense variants, three had paternally inherited loss of function variants and six had maternally inherited loss-of-function variants, while inheritance was unknown for four variants. Four patients had cardiac defects (hypertrophic cardiomyopathy, atrial septal defects, and bicuspid aortic valve). Minor facial anomalies were inconsistent but included a high anterior hairline with a long forehead, broad nasal tip, and ear anomalies. Brainspan analysis showed elevated DIP2C expression in the human neocortex at 10-24 weeks after conception. With the cases presented herein, we provide phenotypic and genotypic data supporting the association between loss-of-function variants in DIP2C with a neurocognitive phenotype.
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Haploinsuficiencia , Trastornos del Desarrollo del Lenguaje , Humanos , Masculino , Femenino , Haploinsuficiencia/genética , Trastornos del Desarrollo del Lenguaje/genética , Trastornos del Desarrollo del Lenguaje/patología , Trastornos del Desarrollo del Lenguaje/fisiopatología , Preescolar , Niño , Lactante , Fenotipo , Predisposición Genética a la EnfermedadRESUMEN
With increasing gene discoveries for severe speech disorders, genomic testing can alter the diagnostic and clinical paradigms, enabling better life outcomes for children and their families. However, evidence on the value of the outcomes generated is lacking, impeding optimal translation into health care. This study aims to estimate the value and uptake of genomic testing for severe childhood speech disorders. A discrete choice experiment was undertaken to elicit preferences for genomic testing from the perspective of the Australian public (n = 951) and parents of children experiencing severe speech disorder (n = 56). Choice attributes associated with genomic testing were identified through focus groups. A Bayesian D-efficient design was used to develop choice scenarios and choice data were analyzed using a panel error component mixed logit model and a latent class model. Statistically significant preferences were identified across all seven attributes. The mean monetary value of the benefits of genomic testing relative to standard diagnostic care in Australia was estimated at AU$7489 (US$5021) and AU$4452 (US$2985) from the perspectives of the Australian public and families with lived experience of severe speech disorders, with a corresponding test uptake of 94.2% and 99.6%. To ensure fair prioritization of genomics, decision-makers need to consider the wide range of risks and benefits associated with genomic information.
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Conducta de Elección , Pruebas Genéticas , Niño , Humanos , Australia , Teorema de Bayes , Trastornos del Habla/diagnóstico , Trastornos del Habla/genética , Encuestas y Cuestionarios , Prioridad del PacienteRESUMEN
Severe speech disorders lead to poor literacy, reduced academic attainment and negative psychosocial outcomes. As early as the 1950s, the familial nature of speech disorders was recognized, implying a genetic basis; but the molecular genetic basis remained unknown. In 2001, investigation of a large three generational family with severe speech disorder, known as childhood apraxia of speech (CAS), revealed the first causative gene; FOXP2. A long hiatus then followed for CAS candidate genes, but in the past three years, genetic analysis of cohorts ascertained for CAS have revealed over 30 causative genes. A total of 36 pathogenic variants have been identified from 122 cases across 3 cohorts in this nascent field. All genes identified have been in coding regions to date, with no apparent benefit at this stage for WGS over WES in identifying monogenic conditions associated with CAS. Hence current findings suggest a remarkable one in three children have a genetic variant that explains their CAS, with significant genetic heterogeneity emerging. Around half of the candidate genes identified are currently supported by medium (6 genes) to strong (9 genes) evidence supporting the association between the gene and CAS. Despite genetic heterogeneity; many implicated proteins functionally converge on pathways involved in chromatin modification or transcriptional regulation, opening the door to precision diagnosis and therapies. Most of the new candidate genes for CAS are associated with previously described neurodevelopmental conditions that include intellectual disability, autism and epilepsy; broadening the phenotypic spectrum to a distinctly milder presentation defined by primary speech disorder in the setting of normal intellect. Insights into the genetic bases of CAS, a severe, rare speech disorder, are yet to translate to understanding the heritability of more common, typically milder forms of speech or language impairment such as stuttering or phonological disorder. These disorders likely follow complex inheritance with polygenic contributions in many cases, rather than the monogenic patterns that underly one-third of patients with CAS. Clinical genetic testing for should now be implemented for individuals with CAS, given its high diagnostic rate, which parallels many other neurodevelopmental disorders where this testing is already standard of care. The shared mechanisms implicated by gene discovery for CAS highlight potential new targets for future precision therapies.
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Trastornos del Habla , Humanos , Trastornos del Habla/genética , Niño , Predisposición Genética a la Enfermedad/genética , Apraxias/genética , Factores de Transcripción Forkhead/genética , Masculino , FemeninoRESUMEN
Pathogenic variants in BRPF1 cause intellectual disability, ptosis and facial dysmorphism. Speech and language deficits have been identified as a manifestation of BRPF1-related disorder but have not been systematically characterized. We provide a comprehensive delineation of speech and language abilities in BRPF1-related disorder and expand the phenotype. Speech and language, and health and medical history were assessed in 15 participants (male = 10, median age = 7 years 4 months) with 14 BRPF1 variants. Language disorders were common (11/12), and most had mild to moderate deficits across receptive, expressive, written, and social-pragmatic domains. Speech disorders were frequent (7/9), including phonological delay (6/9) and disorder (3/9), and childhood apraxia of speech (3/9). All those tested for cognitive abilities had a FSIQ ≥70 (4/4). Participants had vision impairment (13/15), fine (8/15) and gross motor delay (10/15) which often resolved in later childhood, infant feeding impairment (8/15), and infant hypotonia (9/15). We have implicated BRPF1-related disorder as causative for speech and language disorder, including childhood apraxia of speech. Adaptive behavior and cognition were strengths when compared to other monogenic neurodevelopmental chromatin-related disorders. The universal involvement of speech and language impairment is noteable, relative to the high degree of phenotypic variability in BRPF1-related disorder.
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Apraxias , Discapacidad Intelectual , Trastornos del Desarrollo del Lenguaje , Niño , Humanos , Masculino , Proteínas Adaptadoras Transductoras de Señales/genética , Apraxias/genética , Proteínas que Contienen Bromodominio , Proteínas de Unión al ADN/genética , Discapacidad Intelectual/genética , Trastornos del Desarrollo del Lenguaje/genética , Fenotipo , Habla , Trastornos del Habla , FemeninoRESUMEN
PURPOSE: Gene selection for genomic newborn screening (gNBS) underpins the validity, acceptability, and ethical application of this technology. Existing gNBS gene lists are highly variable despite being based on shared principles of gene-disease validity, treatability, and age of onset. This study aimed to curate a gNBS gene list that builds upon existing efforts and provide a core consensus list of gene-disease pairs assessed by multiple expert groups worldwide. METHODS: Our multidisciplinary expert team curated a gene list using an open platform and multiple existing curated resources. We included severe treatable disorders with age of disease onset <5 years with established gene-disease associations and reliable variant detection. We compared the final list with published lists from 5 other gNBS projects to determine consensus genes and to identify areas of discrepancy. RESULTS: We reviewed 1279 genes and 604 met our inclusion criteria. Metabolic conditions comprised the largest group (25%), followed by immunodeficiencies (21%) and endocrine disorders (15%). We identified 55 consensus genes included by all 6 gNBS research projects. Common reasons for discrepancy included variable definitions of treatability and strength of gene-disease association. CONCLUSION: We have identified a consensus gene list for gNBS that can be used as a basis for systematic harmonization efforts internationally.
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Pruebas Genéticas , Genómica , Tamizaje Neonatal , Humanos , Tamizaje Neonatal/métodos , Recién Nacido , Pruebas Genéticas/métodos , Pruebas Genéticas/normas , Genómica/métodos , ConsensoRESUMEN
OBJECTIVES: Speech and language impairments are core features of the neurodevelopmental genetic condition Kleefstra syndrome. Communication has not been systematically examined to guide intervention recommendations. We define the speech, language and cognitive phenotypic spectrum in a large cohort of individuals with Kleefstra syndrome. METHOD: 103 individuals with Kleefstra syndrome (40 males, median age 9.5 years, range 1-43 years) with pathogenic variants (52 9q34.3 deletions, 50 intragenic variants, 1 balanced translocation) were included. Speech, language and non-verbal communication were assessed. Cognitive, health and neurodevelopmental data were obtained. RESULTS: The cognitive spectrum ranged from average intelligence (12/79, 15%) to severe intellectual disability (12/79, 15%). Language ability also ranged from average intelligence (10/90, 11%) to severe intellectual disability (53/90, 59%). Speech disorders occurred in 48/49 (98%) verbal individuals and even occurred alongside average language and cognition. Developmental regression occurred in 11/80 (14%) individuals across motor, language and psychosocial domains. Communication aids, such as sign and speech-generating devices, were crucial for 61/103 (59%) individuals including those who were minimally verbal, had a speech disorder or following regression. CONCLUSIONS: The speech, language and cognitive profile of Kleefstra syndrome is broad, ranging from severe impairment to average ability. Genotype and age do not explain the phenotypic variability. Early access to communication aids may improve communication and quality of life.
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Deleción Cromosómica , Cromosomas Humanos Par 9 , Cognición , Anomalías Craneofaciales , Discapacidad Intelectual , Fenotipo , Humanos , Masculino , Discapacidad Intelectual/genética , Discapacidad Intelectual/fisiopatología , Niño , Adolescente , Femenino , Adulto , Preescolar , Cromosomas Humanos Par 9/genética , Adulto Joven , Lactante , Anomalías Craneofaciales/genética , Anomalías Craneofaciales/fisiopatología , Habla , Trastornos del Habla/genética , Trastornos del Habla/fisiopatología , Lenguaje , Inteligencia/genética , Trastornos del Lenguaje/genética , Trastornos del Lenguaje/fisiopatología , Cardiopatías CongénitasRESUMEN
OBJECTIVE: This study aimed to evaluate the association between human chorionic gonadotropin and adverse pregnancy outcomes. DATA SOURCES: Medline, Embase, PubMed, and Cochrane were searched in November 2021 using Medical Subject Headings (MeSH) and relevant key words. STUDY ELIGIBILITY CRITERIA: This analysis included published full-text studies of pregnant women with serum human chorionic gonadotropin testing between 8 and 28 weeks of gestation, investigating fetal outcomes (fetal death in utero, small for gestational age, preterm birth) or maternal factors (hypertension in pregnancy: preeclampsia, pregnancy-induced hypertension, placental abruption, HELLP syndrome, gestational diabetes mellitus). METHODS: Studies were extracted using REDCap software. The Newcastle-Ottawa scale was used to assess for risk of bias. Final meta-analyses underwent further quality assessment using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) method. RESULTS: A total of 185 studies were included in the final review, including the outcomes of fetal death in utero (45), small for gestational age (79), preterm delivery (62), hypertension in pregnancy (107), gestational diabetes mellitus (29), placental abruption (17), and HELLP syndrome (2). Data were analyzed separately on the basis of categorical measurement of human chorionic gonadotropin and human chorionic gonadotropin measured on a continuous scale. Eligible studies underwent meta-analysis to generate a pooled odds ratio (categorical human chorionic gonadotropin level) or difference in medians (human chorionic gonadotropin continuous scale) between outcome groups. First-trimester low human chorionic gonadotropin levels were associated with preeclampsia and fetal death in utero, whereas high human chorionic gonadotropin levels were associated with preeclampsia. Second-trimester high human chorionic gonadotropin levels were associated with fetal death in utero and preeclampsia. CONCLUSION: Human chorionic gonadotropin levels are associated with placenta-mediated adverse pregnancy outcomes. Both high and low human chorionic gonadotropin levels in the first trimester of pregnancy can be early warning signs of adverse outcomes. Further analysis of human chorionic gonadotropin subtypes and pregnancy outcomes is required to determine the diagnostic utility of these findings in reference to specific cutoff values.
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Desprendimiento Prematuro de la Placenta , Diabetes Gestacional , Síndrome HELLP , Hipertensión Inducida en el Embarazo , Preeclampsia , Nacimiento Prematuro , Embarazo , Humanos , Femenino , Recién Nacido , Preeclampsia/diagnóstico , Desprendimiento Prematuro de la Placenta/epidemiología , Diabetes Gestacional/epidemiología , Placenta , Nacimiento Prematuro/epidemiología , Biomarcadores , Gonadotropina Coriónica , Resultado del Embarazo , Hipertensión Inducida en el Embarazo/epidemiología , Muerte FetalRESUMEN
AIM: To better understand parents' beliefs about causation in cerebral palsy (CP) and the emotions related to those beliefs. METHOD: We surveyed 226 parents of children with CP aged 1 to 18 years, recruited from the Victorian Cerebral Palsy Register, to evaluate their beliefs about the causes of CP, including genetic causes, causes specific to their own child, and their attitudes and emotions in relation to these. RESULTS: Although 92% of participants reported that understanding the causes of their child's CP was important, uncertainty about the cause was expressed by 13%. The most frequently endorsed causal factors, in general and in their own child respectively, were intrapartum hypoxia (81%, 36%) or brain damage (69%, 22%), brain damage during pregnancy (73%, 28%), and preterm birth (66%, 28%). Genetic causes were deemed relevant by 13% of participants and hospital or professional error by 16%. Parents shared related feelings of anger (59%), sadness (80%), guilt (61%), and confusion (53%); parental anger was more likely when their child's CP was attributed to intrapartum events. INTERPRETATION: Substantial parental interest in understanding the causes of CP, together with uncertainty about the causes, parents' causal attributions, and significant emotional sequelae, highlight a strong need for provision of information and support for families of children recently diagnosed with CP. WHAT THIS PAPER ADDS: Understanding the causes of their child's cerebral palsy (CP) was important to parents. Parents most often endorsed intrapartum factors as a cause of CP. Parents reported experiencing strong emotions about the causes of their child's CP.
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Parálisis Cerebral , Nacimiento Prematuro , Niño , Femenino , Embarazo , Humanos , Recién Nacido , Parálisis Cerebral/etiología , Parálisis Cerebral/psicología , Padres/psicología , Emociones , CausalidadRESUMEN
AIM: To investigate parents' preferences and motivations for receiving and discussing prognostic genetic test results. METHOD: We used a cross-sectional, interpretive description qualitative study design. We collected data through semi-structured interviews with Australian parents, which we analysed using reflexive thematic analysis. RESULTS: Parents (n = 32) had a child or children with a genetic neurodevelopmental condition, such as fragile X syndrome, DiGeorge (22q11.2 deletion) syndrome, or Angelman syndrome. Parents of mildly impacted or older children were tolerant to prognostic uncertainty. Parents found conversations about their child's prognosis emotional and preferred to discuss their child's potential strengths and challenges. While most were enthusiastic about prognostic tests and described many motivations for testing, the potential for prognostic information to contribute to a loss of hope and stigmatizing societal views were also discussed. INTERPRETATION: Parents had mixed preferences and motivations for acquiring prognostic genetic information about their child, contrasting evidence in other contexts such as cancer where parents typically have minimal tolerance of uncertainty. Health professionals should consider strength-based framing of prognostic information gained from current and emerging technologies when returning results to families. WHAT THIS PAPER ADDS: Parents had varied views about receiving prognostic information on their children's neurodevelopmental condition. Some parents preferred prognostic uncertainty about their children's genetic neurodevelopmental condition.