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Trio-based exome sequencing reveals a high rate of the de novo variants in intellectual disability.

ABSTRACT: Intellectual disability (ID), a neurodevelopmental disorder affecting 1-3% of the general population, is characterized by limitations in both intellectual function and adaptive skills. The high number of conditions associated with ID underlines its heterogeneous origin and reveals the difficulty of obtaining a rapid and accurate genetic diagnosis. However, the Next Generation Sequencing, and the whole exome sequencing (WES) in particular, has boosted the diagnosis rate associated with ID. In this study, WES performed on 244 trios of patients clinically diagnosed with isolated or syndromic ID and their respective unaffected parents has allowed the identification of the underlying genetic basis of ID in 64 patients, yielding a diagnosis rate of 25.2%. Our results suggest that trio-based WES facilitates ID's genetic diagnosis, particularly in patients who have been extensively waiting for a definitive molecular diagnosis. Moreover, genotypic information from parents provided by trio-based WES enabled the detection of a high percentage (61.5%) of de novo variants inside our cohort. Establishing a quick genetic diagnosis of ID would allow early intervention and better clinical management, thus improving the quality of life of these patients and their families.

SUBMITTER: Brea-Fernandez AJ

PROVIDER: S-EPMC9349217 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Trio-based exome sequencing reveals a high rate of the de novo variants in intellectual disability.

Brea-Fernández Alejandro J AJ Álvarez-Barona Miriam M Amigo Jorge J Tubío-Fungueiriño María M Caamaño Pilar P Fernández-Prieto Montserrat M Barros Francisco F De Rubeis Silvia S Buxbaum Joseph J Carracedo Ángel Á

European journal of human genetics : EJHG 20220323 8

Intellectual disability (ID), a neurodevelopmental disorder affecting 1-3% of the general population, is characterized by limitations in both intellectual function and adaptive skills. The high number of conditions associated with ID underlines its heterogeneous origin and reveals the difficulty of obtaining a rapid and accurate genetic diagnosis. However, the Next Generation Sequencing, and the whole exome sequencing (WES) in particular, has boosted the diagnosis rate associated with ID. In thi ...[more]

PMID: 35322241

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Project description:Understanding the genetic basis of developmental delay (DD) and intellectual disability (ID) remains a considerable clinical challenge. This study evaluated the clinical application of trio whole exome sequencing (WES) in children diagnosed with DD/ID. The study comprised 173 children with unexplained DD/ID. The participants underwent trio-WES and their demographic, clinical, and genetic characteristics were evaluated. Based on their clinical features, the participants were classified into two groups for further analysis: a syndromic DD/ID group and a non-syndromic DD/ID group. The genetic diagnostic yield of the 173 children diagnosed with DD/ID was 49.7% (86/173). This included 58 pathogenic or likely pathogenic single nucleotide variants (SNVs) in 41 genes identified across 54 individuals (31.2%) through trio-WES. Among these, 22 SNVs had not been previously reported. Additionally, 30 copy number variations (CNVs) were detected in 36 individuals (20.8%). The diagnostic yield in the syndromic DD/ID group was higher than that in the non-syndromic DD/ID group (57.8% vs. 47.2%, P < 0.001). Within the syndromic DD/ID subgroup, the diagnostic yield of the DD/ID with epilepsy subgroup (83.9%) was significantly higher than those of the other subgroups (P < 0.001). Based on the analysis of the individuals' clinical phenotypes, the individuals with facial dysmorphism shown a higher diagnostic yield (68.2%, P < 0.001). The diagnostic yield of SNVs was higher in the individuals with DD/ID accompanied by epilepsy, whereas the diagnostic yield of CNVs was higher in the DD/ID without epilepsy group. Similarly, the diagnostic yield of de novo SNVs was higher in the DD/ID with epilepsy group, while the diagnostic yield of de novo CNVs was higher in the DD/ID without epilepsy group (all P < 0.001). Trio-WES is a crucial tool for the genetic diagnosis of DD/ID, demonstrating a diagnostic yield of up to 49.7%. De novo variants in autosomal dominant genes are significant contributors to DD/ID, particularly in non-consanguineous families.

Dataset Information

Trio-based exome sequencing reveals a high rate of the de novo variants in intellectual disability.

Publications

Trio-based exome sequencing reveals a high rate of the de novo variants in intellectual disability.

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