Comparison of the diagnostic yield of aCGH and genome-wide sequencing across different neurodevelopmental disorders

Francisco Martinez-Granero,Isabel Lorda-Sanchez,Marta Rodríguez De Alba,Maria Jose Trujillo-Tiebas,Cristina Rodilla,Rosa Riveiro-Alvarez,Saoud Tahsin-Swafiri,Ana Arteche,Ana Bustamante-Aragones,Almudena Avila-Fernandez,Elvira Rodríguez-Pinilla,Carmen Ayuso,Berta Almoguera,Fiona Blanco-Kelly,Carolina Sanchez-Jimeno

doi:10.1038/s41525-021-00188-7

Francisco Martinez-Granero, Isabel Lorda-Sanchez + Show 13 more

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https://doi.org/10.1038/s41525-021-00188-7

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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.

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The term neurodevelopmental disorder (NDD) has been applied to a very broad group of disabilities involving the disruption of brain and neurocognitive development and includes a wide range of neurological and psychiatric problems that are clinically and causally disparate[1].In its latest version, the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) classifies a heterogeneous group of conditions as neurodevelopmental disorders (NDDs): Global developmental delay/intellectual disability (GDD/ID); Autism spectrum disorder (ASD); Attention deficit/hyperactivity disorders (ADHD); Communication disorders; Specific learning disorders; and motor disorders[2]
Srivastava et al recently published the results of a meta-analysis of the diagnostic yield of whole exome sequencing (WES) reported in NDDs and concluded that this technique is superior than CMA and should be used as the first-tier test[5]
In order to provide additional evidence for the use of next generation sequencing (NGS) as the preferred test in NDDs, in the present work, we used genomic data generated on array CGH (aCGH) and clinical exome sequencing between 2015 and 2019, as part of our genetic diagnostic algorithm, to delineate the diagnostic yield of each technology in NDDs, and across its spectrum of disorders, and compare the performance of both

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The term neurodevelopmental disorder (NDD) has been applied to a very broad group of disabilities involving the disruption of brain and neurocognitive development and includes a wide range of neurological and psychiatric problems that are clinically and causally disparate[1].In its latest version, the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) classifies a heterogeneous group of conditions as NDD: Global developmental delay/intellectual disability (GDD/ID); Autism spectrum disorder (ASD); Attention deficit/hyperactivity disorders (ADHD); Communication disorders; Specific learning disorders; and motor disorders[2]. The genetic architecture of NDDs is complex with monogenic and multifactorial inheritance[1,3,4]; with virtually any type of genetic variation involved, and over 2000 genes described to date (Deciphering Developmental Disorders, www.ddduk.org). This complexity typically requires iterative genetic testing, which frequently results in what has been called a “diagnostic odyssey”, where after a lengthy and costly process, as high as 50% of patients do not benefit of an etiological diagnosis[4,5]. Establishing a precise and timely diagnosis is critical for patient and family management and for exploring potential therapeutic interventions[6,7]

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