Martinez-Granero Francisco, Blanco-Kelly Fiona, Sanchez-Jimeno Carolina, Avila-Fernandez Almudena, Arteche Ana, Bustamante-Aragones Ana, Rodilla Cristina, Rodríguez-Pinilla Elvira, Riveiro-Alvarez Rosa, Tahsin-Swafiri Saoud, Trujillo-Tiebas Maria Jose, Ayuso Carmen, Rodríguez de Alba Marta, Lorda-Sanchez Isabel, Almoguera Berta
Department of Genetics and Genomics, IIS-Fundación Jiménez Díaz University Hospital, Madrid, Spain.
Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain.
NPJ Genom Med. 2021 Mar 25;6(1):25. doi: 10.1038/s41525-021-00188-7.
Most consensus recommendations for the genetic diagnosis of neurodevelopmental disorders (NDDs) do not include the use of next generation sequencing (NGS) and are still based on chromosomal microarrays, such as comparative genomic hybridization array (aCGH). This study compares the diagnostic yield obtained by aCGH and clinical exome sequencing in NDD globally and its spectrum of disorders. To that end, 1412 patients clinically diagnosed with NDDs and studied with aCGH were classified into phenotype categories: global developmental delay/intellectual disability (GDD/ID); autism spectrum disorder (ASD); and other NDDs. These categories were further subclassified based on the most frequent accompanying signs and symptoms into isolated forms, forms with epilepsy; forms with micro/macrocephaly and syndromic forms. Two hundred and forty-five patients of the 1412 were subjected to clinical exome sequencing. Diagnostic yield of aCGH and clinical exome sequencing, expressed as the number of solved cases, was compared for each phenotype category and subcategory. Clinical exome sequencing was superior than aCGH for all cases except for isolated ASD, with no additional cases solved by NGS. Globally, clinical exome sequencing solved 20% of cases (versus 5.7% by aCGH) and the diagnostic yield was highest for all forms of GDD/ID and lowest for Other NDDs (7.1% versus 1.4% by aCGH) and ASD (6.1% versus 3% by aCGH). In the majority of cases, diagnostic yield was higher in the phenotype subcategories than in the mother category. These results suggest that NGS could be used as a first-tier test in the diagnostic algorithm of all NDDs followed by aCGH when necessary.
大多数关于神经发育障碍（NDDs）基因诊断的共识性建议并不包括使用下一代测序（NGS），仍然基于染色体微阵列，如比较基因组杂交阵列（aCGH）。本研究比较了aCGH和临床外显子组测序在全球范围内对NDDs的诊断率及其疾病谱。为此，将1412例临床诊断为NDDs并接受aCGH检测的患者分为表型类别：全面发育迟缓/智力残疾（GDD/ID）；自闭症谱系障碍（ASD）；以及其他NDDs。这些类别根据最常见的伴随体征和症状进一步细分为孤立型、伴有癫痫型、伴有小头/大头型和综合征型。1412例患者中有245例接受了临床外显子组测序。比较了每种表型类别和亚类中aCGH和临床外显子组测序的诊断率（以确诊病例数表示）。除孤立型ASD外，临床外显子组测序在所有病例中均优于aCGH，NGS未解决额外病例。总体而言，临床外显子组测序解决了20%的病例（aCGH为5.7%），所有形式的GDD/ID诊断率最高，其他NDDs（aCGH为7.1%对1.4%）和ASD（aCGH为6.1%对3%）最低。在大多数情况下，表型亚类的诊断率高于母类。这些结果表明，NGS可作为所有NDDs诊断算法中的一线检测方法，必要时随后进行aCGH检测。
