Mellone Simona, Puricelli Chiara, Vurchio Denise, Ronzani Sara, Favini Simone, Maruzzi Arianna, Peruzzi Cinzia, Papa Amanda, Spano Alice, Sirchia Fabio, Mandrile Giorgia, Pelle Alessandra, Rasmini Paolo, Vercellino Fabiana, Zonta Andrea, Rabbone Ivana, Dianzani Umberto, Viri Maurizio, Giordano Mara
Laboratory of Genetics, Clinical Biochemistry, University Hospital Maggiore della Carità, Novara, Italy.
Department of Health Sciences, Università del Piemonte Orientale, Novara, Italy.
Front Genet. 2022 Aug 11;13:875182. doi: 10.3389/fgene.2022.875182. eCollection 2022.
Neurodevelopmental disorders comprise a clinically and genetically heterogeneous group of conditions that affect 2%-5% of children and represents a public health challenge due to complexity of the etiology. Only few patients with unexplained syndromic and non-syndromic NDDs receive a diagnosis through first-tier genetic tests as array-CGH and the search for CGG expansion. The aim of this study was to evaluate the clinical performance of a targeted next-generation sequencing (NGS) gene panel as a second-tier test in a group of undiagnosed patients with NDDs. A 221-gene next-generation sequencing custom panel was designed and used to analyze a cohort of 338 patients with a broad spectrum of NDDs (202 males and 136 females) including Intellectual Disability (ID), Autism Spectrum Disorders (ASD), Epilepsy, language and motor disorders. A molecular diagnosis was established in 71 patients (21%) and a origin was present in 38 (64.4%) of the available trios. The diagnostic yield was significantly higher in females than in males (29.4% vs. 15.3%; = 0.0019) in particular in ASD (36.8% vs. 7.6%; = 0.0026) and Epilepsy (38.9% vs. 14.4% = 0.001). The most involved genes were , , , , , and altered in more than two patients and accounting for the 19.7% of the diagnosis. Our findings showed that this NGS panel represents a powerful and affordable clinical tool, significantly increasing the diagnostic yield in patients with different form of NDDs in a cost- and time-effective manner without the need of large investments in data storage and bioinformatic analysis.
神经发育障碍是一组临床和遗传异质性疾病，影响2%-5%的儿童，由于病因复杂，这是一项公共卫生挑战。只有少数不明原因的综合征性和非综合征性神经发育障碍患者通过一线基因检测（如阵列比较基因组杂交和寻找CGG扩增）获得诊断。本研究的目的是评估靶向新一代测序（NGS）基因panel作为一组未确诊神经发育障碍患者的二线检测的临床性能。设计了一个包含221个基因的新一代测序定制panel，并用于分析338例患有广泛神经发育障碍的患者队列（202例男性和136例女性），包括智力残疾（ID）、自闭症谱系障碍（ASD）、癫痫、语言和运动障碍。71例患者（21%）确诊，38例（64.4%）的可用三联体有明确病因。女性的诊断率显著高于男性（29.4%对15.3%；P=0.0019），尤其是在ASD（36.8%对7.6%；P=0.0026）和癫痫（38.9%对14.4%，P=0.001）中。最常受累的基因是，，，，，，在两名以上患者中发生改变，占诊断的19.7%。我们的研究结果表明，该NGS panel是一种强大且经济实惠的临床工具，以具有成本效益和时间效益的方式显著提高了不同形式神经发育障碍患者的诊断率，而无需在数据存储和生物信息分析方面进行大量投资。
