Verbitsky Miguel, Sanna-Cherchi Simone, Fasel David A, Levy Brynn, Kiryluk Krzysztof, Wuttke Matthias, Abraham Alison G, Kaskel Frederick, Köttgen Anna, Warady Bradley A, Furth Susan L, Wong Craig S, Gharavi Ali G
J Clin Invest. 2015 May;125(5):2171-8. doi: 10.1172/JCI80877. Epub 2015 Apr 20.
There is frequent uncertainty in the identification of specific etiologies of chronic kidney disease (CKD) in children. Recent studies indicate that chromosomal microarrays can identify rare genomic imbalances that can clarify the etiology of neurodevelopmental and cardiac disorders in children; however, the contribution of unsuspected genomic imbalance to the incidence of pediatric CKD is unknown.
We performed chromosomal microarrays to detect genomic imbalances in children enrolled in the Chronic Kidney Disease in Children (CKiD) prospective cohort study, a longitudinal prospective multiethnic observational study of North American children with mild to moderate CKD. Patients with clinically detectable syndromic disease were excluded from evaluation. We compared 419 unrelated children enrolled in CKiD to multiethnic cohorts of 21,575 children and adults that had undergone microarray genotyping for studies unrelated to CKD.
We identified diagnostic copy number disorders in 31 children with CKD (7.4% of the cohort). We detected 10 known pathogenic genomic disorders, including the 17q12 deletion HNF1 homeobox B (HNF1B) and triple X syndromes in 19 of 419 unrelated CKiD cases as compared with 98 of 21,575 control individuals (OR 10.8, P = 6.1 × 10⁻²⁰). In an additional 12 CKiD cases, we identified 12 likely pathogenic genomic imbalances that would be considered reportable in a clinical setting. These genomic imbalances were evenly distributed among patients diagnosed with congenital and noncongenital forms of CKD. In the vast majority of these cases, the genomic lesion was unsuspected based on the clinical assessment and either reclassified the disease or provided information that might have triggered additional clinical care, such as evaluation for metabolic or neuropsychiatric disease.
A substantial proportion of children with CKD have an unsuspected genomic imbalance, suggesting genomic disorders as a risk factor for common forms of pediatric nephropathy. Detection of pathogenic imbalances has practical implications for personalized diagnosis and health monitoring in this population.
ClinicalTrials.gov NCT00327860.
This work was supported by the NIH, the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Child Health and Human Development, and the National Heart, Lung, and Blood Institute.
儿童慢性肾脏病（CKD）特定病因的识别常常存在不确定性。近期研究表明，染色体微阵列可识别罕见的基因组失衡，从而阐明儿童神经发育障碍和心脏疾病的病因；然而，未被怀疑的基因组失衡对儿童CKD发病率的影响尚不清楚。
我们对参与儿童慢性肾脏病（CKiD）前瞻性队列研究的儿童进行了染色体微阵列检测，以检测基因组失衡。CKiD是一项针对北美轻度至中度CKD儿童的纵向前瞻性多民族观察性研究。临床可检测到综合征性疾病的患者被排除在评估之外。我们将419名参与CKiD研究的无亲缘关系儿童与21575名儿童和成人的多民族队列进行了比较，后者因与CKD无关的研究进行了微阵列基因分型。
我们在31名CKD儿童（占队列的7.4%）中发现了诊断性拷贝数异常。我们在419例无亲缘关系的CKiD病例中的19例中检测到10种已知的致病性基因组疾病，包括17q12缺失的肝细胞核因子1β（HNF1B）和XXX综合征，而在21575名对照个体中的98例中检测到（比值比10.8，P = 6.1×10⁻²⁰）。在另外12例CKiD病例中，我们发现了12种可能致病性的基因组失衡，在临床环境中这些失衡将被视为可报告的。这些基因组失衡在诊断为先天性和非先天性CKD形式的患者中均匀分布。在绝大多数这些病例中，基于临床评估未怀疑到基因组病变，而这些病变要么对疾病进行了重新分类，要么提供了可能触发额外临床护理的信息，例如对代谢或神经精神疾病的评估。
相当一部分CKD儿童存在未被怀疑的基因组失衡，提示基因组疾病是儿童常见肾病形式的一个危险因素。致病性失衡的检测对该人群的个性化诊断和健康监测具有实际意义。
ClinicalTrials.gov NCT00327860。
本研究得到了美国国立卫生研究院（NIH）、国立糖尿病、消化和肾脏疾病研究所（NIDDK）、国立儿童健康与人类发展研究所以及国立心肺血液研究所的支持。
