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Observational Study
. 2024 Oct 11;15(10):1310.
doi: 10.3390/genes15101310.

Whole Exome Sequencing and Panel-Based Analysis in 176 Spanish Children with Neurodevelopmental Disorders: Focus on Autism Spectrum Disorder and/or Intellectual Disability/Global Developmental Delay

Ariadna Sánchez Suárez  1   2 , Beatriz Martínez Menéndez  2   3 , Eduardo Escolar Escamilla  2   3 , Francisco J Martínez Sarries  3 , Miren Iranzu Esparza Garrido  4 , Belén Gil-Fournier  5 , Soraya Ramiro León  5 , Bárbara Rubio Gribble  2   4 , Juan F Quesada Espinosa  6 , Andrés J Alcaraz Romero  2   4
Affiliations
Observational Study

Whole Exome Sequencing and Panel-Based Analysis in 176 Spanish Children with Neurodevelopmental Disorders: Focus on Autism Spectrum Disorder and/or Intellectual Disability/Global Developmental Delay

Ariadna Sánchez Suárez et al. Genes (Basel). .

Abstract

Background: Neurodevelopmental disorders (NDDs) represent a significant challenge in pediatric genetics, often requiring advanced diagnostic tools for the accurate identification of genetic variants.

Objectives: To determine the diagnostic yield of whole exome sequencing (WES) with targeted gene panels in children with neurodevelopmental disorders (NDDs).

Methods: This observational, prospective study included a total of 176 Spanish-speaking pediatric patients with neurodevelopmental disorders (NDDs), encompassing intellectual disability (ID), global developmental delay (GDD), and/or autism spectrum disorder (ASD). Participants were recruited from January 2019 to January 2023 at a University Hospital in Madrid, Spain. Clinical and sociodemographic variables were recorded, along with genetic study results. The age range of the subjects was 9 months to 16 years, and the percentage of males was 72.1%. The diagnostic yield of whole exome sequencing (WES) was calculated both before and after parental testing via Sanger DNA sequencing.

Results: The study included 176 children: 67 (38.1%) with ID, 62 (35.2%) with ASD, and 47 (26.7%) with ASD + ID. The diagnostic yield of proband-only exome sequencing was 12.5% (22/176). By group, the diagnostic yield of proband-only exome sequencing was 3.2% in the ASD, 12.7% in the ASD + ID, and 20.8% in the ID group. Variants of uncertain significance (VUS) were found in 39.8% (70/176). After parental testing, some variants were reclassified as "likely pathogenic", increasing the diagnostic yield by 4.6%, with an overall diagnostic yield of 17.1%. Diagnostic yield was higher in patients with syndromic ID (70.6%% vs. 29.4%; p = 0.036).

Conclusions: A sequential approach utilizing WES followed by panel-based analysis, starting with the index case and, when appropriate, including the parents, proves to be a cost-effective strategy. WES is particularly suitable for complex conditions, as it allows for the identification of potentially causative genes beyond those covered by targeted panels, providing a more comprehensive analysis. Including parental testing enhances the diagnostic yield and improves accuracy, especially in cases with variants of uncertain significance (VUS), thereby advancing our understanding of NDDs.

Keywords: autism spectrum disorder; diagnostic yield; intellectual disability; neurodevelopmental disorders; variants of uncertain significance; whole exome sequencing.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Flowchart.
Figure 2
Figure 2
Classification of patients by diagnostic subgroups. ID: intellectual disability; ASD: autism spectrum disorder; and GDD: global developmental delay.
Figure 3
Figure 3
Dysmorphic features/congenital abnormalities. The frequency of dysmorphic features/congenital anomalies detected in the patients is described.
Figure 4
Figure 4
Associated comorbidity in patients. ADHD: attention deficit hyperactivity disorder.
See this image and copyright information in PMC

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