Neuropsychiatric risk in children with intellectual disability of genetic origin: IMAGINE, a UK national cohort study,The Lancet Psychiatry

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Neuropsychiatric risk in children with intellectual disability of genetic origin: IMAGINE, a UK national cohort study
The Lancet Psychiatry ( IF 30.8 ) Pub Date : 2022-08-03 , DOI: 10.1016/s2215-0366(22)00207-3
Jeanne Wolstencroft ₁ , Francesca Wicks ₂ , Ramya Srinivasan ₃ , Sarah Wynn ₄ , Tamsin Ford ₂ , Kate Baker ₅ , Samuel J R A Chawner ₆ , Jeremy Hall ₇ , Marianne B M van den Bree ₇ , Michael J Owen ₇ , , David Skuse ₁ , F Lucy Raymond ₈

Affiliation

NIHR BRC Great Ormond Street Institute of Child Health, University College London, London, UK.
School of Clinical Medicine, University of Cambridge, Cambridge, UK.
NIHR BRC Great Ormond Street Institute of Child Health, University College London, London, UK; UCL Division of Psychiatry, University College London, London, UK.
UNIQUE Charity, Oxted, UK.
School of Clinical Medicine, University of Cambridge, Cambridge, UK; Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK; MRC Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, UK.
Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK; Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK; Cardiff University Centre for Human Developmental Science, School of Psychology, Cardiff University, Cardiff, UK.
Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK; Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK.
School of Clinical Medicine, University of Cambridge, Cambridge, UK; Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK; NIHR Bioresource, Cambridge Biomedical Campus, Cambridge, UK.

Background

Children with intellectual disability frequently have multiple co-morbid neuropsychiatric conditions and poor physical health. Genomic testing is increasingly recommended as a first-line investigation for these children. We aim to determine the effect of genomics, inheritance, and socioeconomic deprivation on neuropsychiatric risk in children with intellectual disability of genetic origin as compared with the general population.

Methods

IMAGINE is a prospective cohort study using online mental health and medical assessments in a cohort of 3407 UK participants with intellectual disability and pathogenic genomic variants as identified by the UK's National Health Service (NHS). Our study is on a subset of these participants, including all children aged 4–19 years. We collected diagnostic genomic reports from NHS records and asked primary caregivers to provide an assessment of their child using the Development and Well-Being Assessment (DAWBA), the Strengths and Difficulties Questionnaire (SDQ), the Adaptive Behaviour Assessment System 3 (ABAS-3), and a medical history questionnaire. Each child was assigned a rank based on their postcode using the index of multiple deprivation (IMD). We compared the IMAGINE cohort with the 2017 National Survey of Children's Mental Health in England. The main outcomes of interest were mental health and neurodevelopment according to the DAWBA and SDQ.

Findings

We recruited 2770 children from the IMAGINE study between Oct 1, 2014 and June 30, 2019, of whom 2397 (86·5%) had a basic assessment of their mental health completed by their families and 1277 (46·1%) completed a medical history questionnaire. The mean age of participants was 9·2 years (SD 3·9); 1339 (55·9%) were boys and 1058 (44·1%) were girls. 355 (27·8%) of 1277 reported a seizure disorder and 814 (63·7%) reported movement or co-ordination problems. 1771 (73·9%) of 2397 participants had a pathogenic copy number variant (CNV) and 626 (26·1%) had a pathogenic single nucleotide variant (SNV). Participants were representative of the socioeconomic spectrum of the UK general population. The relative risk (RR) of co-occurring neuropsychiatric diagnoses, compared with the English national population, was high: autism spectrum disorder RR 29·2 (95% CI 23·9–36·5), ADHD RR 13·5 (95% CI 11·1–16·3). In children with a CNV, those with a familial variant tended to live in more socioeconomically deprived areas than those with a de novo variant. Both inheritance and socioeconomic deprivation contributed to neuropsychiatric risk in those with a CNV.

Interpretation

Children with genomic variants and intellectual disability are at an increased risk of neuropsychiatric difficulties. CNV variant inheritance and socioeconomic deprivation also contribute to the risk. Early genomic investigations of children with intellectual disability could facilitate the identification of the most vulnerable children. Additionally, harnessing parental expertise using online DAWBA assessments could rapidly identify children with exceptional needs to child mental health services.

Funding

UK Medical Research Council and Medical Research Foundation.

中文翻译：

遗传性智力障碍儿童的神经精神风险：IMAGINE，英国国家队列研究

背景

智力障碍儿童经常患有多种神经精神疾病并且身体健康状况不佳。基因组测试越来越被推荐作为这些儿童的一线检查。我们的目的是确定与普通人群相比，基因组学、遗传和社会经济剥夺对遗传性智力障碍儿童的神经精神风险的影响。

方法

IMAGINE 是一项前瞻性队列研究，使用在线心理健康和医学评估，对 3407 名英国参与者进行队列研究，这些参与者患有英国国家卫生服务 (NHS) 确定的智力障碍和致病基因组变异。我们的研究对象是这些参与者的一部分，包括所有 4 至 19 岁的儿童。我们从 NHS 记录中收集了诊断基因组报告，并要求主要看护者使用发育和福祉评估 (DAWBA)、优势和困难问卷 (SDQ)、适应性行为评估系统 3 (ABAS-3) 对其孩子进行评估）和病史调查问卷。每个孩子都根据其邮政编码使用多重剥夺指数（IMD）进行排名。我们将 IMAGINE 队列与 2017 年英国儿童心理健康国家调查进行了比较。根据 DAWBA 和 SDQ，主要关注的结果是心理健康和神经发育。

发现

我们在2014年10月1日至2019年6月30日期间从IMAGINE研究中招募了2770名儿童，其中2397名（86·5%）由家人完成了心理健康的基本评估，1277名（46·1%）完成了心理健康评估。病史问卷。参与者的平均年龄为 9·2 岁 (SD 3·9)；男生1339人（55·9%），女生1058人（44·1%）。 1277 人中有 355 人 (27·8%) 报告有癫痫症，814 人 (63·7%) 报告有运动或协调问题。 2397 名参与者中有 1771 名 (73·9%) 存在致病性拷贝数变异 (CNV)，626 名 (26·1%) 存在致病性单核苷酸变异 (SNV)。参与者代表了英国普通民众的社会经济阶层。与英国全国人口相比，同时发生神经精神疾病的相对风险 (RR) 较高：自闭症谱系障碍 RR 29·2 (95% CI 23·9–36·5)，ADHD RR 13·5 (95 % CI 11·1–16·3)。在患有 CNV 的儿童中，那些有家族变异的儿童往往比那些有新发变异的儿童生活在社会经济条件更为贫困的地区。遗传和社会经济剥夺都会增加 CNV 患者的神经精神风险。