Zaks Nina, Mahjani Behrang, Reichenberg Abraham, Birnbaum Rebecca
Department of Child and Adolescent Psychiatry, NYU Langone Health.
Department of Psychiatry, Icahn School of Medicine at Mount Sinai.
medRxiv. 2024 Jul 16:2024.07.16.24310489. doi: 10.1101/2024.07.16.24310489.
Rare copy number variants (CNVs) are pathogenic for neurodevelopmental disorders (NDDs) and effect neurocognitive impairment. In aggregate, NDD CNVs may present in up to 2% of population cohorts with implications for neuropsychiatric disease risk and cognitive health. However, analyses of NDD CNVs in biobanks or population cohorts have been hindered by limited clinical or cognitive phenotypes, and a lack of ancestral diversity. In the current proof-of-concept study, NDD CNV carriers were recontacted from Bio, a multi-ancestry biobank derived from the Mount Sinai healthcare system, to enable 'deep phenotyping' beyond electronic health record outcomes.
From Bio biobank, 892 adult participants were recontacted, including 335 harboring NDD CNVs, 217 with schizophrenia and 340 neurotypical controls as comparators. Clinical and cognitive assessments were administered to each recruited participant.
Seventy-three participants completed study assessments (mean age=48.8 years; 66% female; 36% African, 26% European, 34% Hispanic), or 8% of the recontacted subset, including 30 NDD CNV carriers across 15 loci. Among NDD CNV carriers, assessments indicated 40% with mood and anxiety disorders, 30% with learning disorders, and 13% with a history of special education. NDD CNV carriers were significantly cognitively impaired compared to controls on digit span backwards (Beta=-1.76, FDR=0.04) and digit span sequencing (Beta=-2.01, FDR=0.04).
Feasibility of "recall-by-genotype" from a multi-ancestry biobank was established for NDD CNV carriers, along with comparator groups. The current study corroborated past reports of NDD CNVs effects of cognitive impairment, while elucidating clinical phenotypes for recalled individuals. Future "recall-by-genotype" studies may further facilitate clinical characterization of disease-relevant genomic variants.
罕见拷贝数变异（CNV）是神经发育障碍（NDD）的致病因素，并会导致神经认知障碍。总体而言，NDD CNV可能存在于高达2%的人群队列中，这对神经精神疾病风险和认知健康具有影响。然而，生物样本库或人群队列中NDD CNV的分析受到临床或认知表型有限以及缺乏祖先多样性的阻碍。在当前的概念验证研究中，从Bio（一个源自西奈山医疗系统的多祖先生物样本库）重新联系了NDD CNV携带者，以实现超越电子健康记录结果的“深度表型分析”。
从Bio生物样本库中重新联系了892名成年参与者，其中包括335名携带NDD CNV的参与者、217名精神分裂症患者和340名神经典型对照者作为比较对象。对每位招募的参与者进行了临床和认知评估。
73名参与者完成了研究评估（平均年龄 = 48.8岁；66%为女性；36%为非洲裔，26%为欧洲裔，34%为西班牙裔），占重新联系子集的8%，其中包括15个位点的30名NDD CNV携带者。在NDD CNV携带者中，评估显示40%患有情绪和焦虑障碍，30%患有学习障碍，13%有特殊教育史。与对照组相比，NDD CNV携带者在倒背数字广度（β = -1.76，错误发现率 = 0.04）和数字广度排序（β = -2.01，错误发现率 = 0.04）方面存在显著的认知障碍。
已确定从多祖先生物样本库中对NDD CNV携带者以及比较组进行“基因型召回”的可行性。当前研究证实了过去关于NDD CNV对认知障碍影响的报道，同时阐明了召回个体的临床表型。未来的“基因型召回”研究可能会进一步促进与疾病相关的基因组变异的临床特征分析。
