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

Brea‐Fernández, Alejandro; Álvarez-Barona, Miriam; Amigo, Jorge; Tubío-Fungueiriño, María; Caamaño, Pilar; Fernández-Prieto, Montserrat; Barros, Francisco; Rubeis, Silvia De; Buxbaum, Joseph D.; Carracedo, Ángel

doi:10.1038/s41431-022-01087-w

Cited by 10 publications

(10 citation statements)

References 50 publications

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“…The results also supported the high correlation between de novo occurrence of the variants and their pathogenicity, with 86.1% of the triotested pathogenic variants (149/173) occurring de novo. This high rate of de novo variants was consistent with previous studies, which reported the rate of de novo variants 80% and 61.5%, respectively (8,9).…”

Section: Discussionsupporting

confidence: 92%

“…NGS-based trio tests can determine novel candidate genes and variants and find causal pathogenic variants, which can be overlooked during variant interpretation. Exome-trio has recently been widely used, and studies have reported its clinical usefulness for the diagnosis of NDD (7)(8)(9). In these studies, various number of patients with NDD were trio-tested (54-244 patients).…”

Section: Discussionmentioning

confidence: 99%

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Analysis of trio test in neurodevelopmental disorders

Kim

Kwon²,

Lee³

et al. 2022

Front. Pediatr.

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BackgroundTrio test has been widely used for diagnosis of various hereditary disorders. We aimed to investigate the contribution of trio test in genetically diagnosing neurodevelopmental disorders (NDD).MethodsWe retrospectively reviewed 2,059 NDD cases with genetic test results. The trio test was conducted in 563 cases. Clinical usefulness, optimal timing, and methods for the trio test were reviewed.ResultsPathogenic or likely pathogenic variants were detected in 112 of 563 (19.9%) patients who underwent the trio test. With trio test results, the overall diagnostic yield increased by 5.4% (112/2,059). Of 165 de novo variants detected, 149 were pathogenic and we detected 85 novel pathogenic variants. Pathogenic, de novo variants were frequently detected in CDKL5, ATP1A3, and STXBP1.ConclusionThe trio test is an efficient method for genetically diagnosing NDD. We identified specific situations where a certain trio test is more appropriate, thereby providing a guide for clinicians when confronted with variants of unknown significance of specific genes.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Analysis of trio test in neurodevelopmental disorders

Kim

Kwon²,

Lee³

et al. 2022

Front. Pediatr.

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“…The diagnostic success rate of WES is reportedly 25–44% [ 20 , 21 , 22 ]. WES enables the identification of pathogenic variants, including copy number variants (CNVs), and genetic heterogeneity of de novo variants in NDDs, highlighting trio exome sequencing as an effective diagnostic tool for NDDs [ 23 ].…”

Section: Major Advances In Epilepsy Genomicsmentioning

confidence: 99%

Genetic Testing in Children with Developmental and Epileptic Encephalopathies: A Review of Advances in Epilepsy Genomics

et al. 2023

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Advances in disease-related gene discovery have led to tremendous innovations in the field of epilepsy genetics. Identification of genetic mutations that cause epileptic encephalopathies has opened new avenues for the development of targeted therapies. Clinical testing using extensive gene panels, exomes, and genomes is currently accessible and has resulted in higher rates of diagnosis and better comprehension of the disease mechanisms underlying the condition. Children with developmental disabilities have a higher risk of developing epilepsy. As our understanding of the mechanisms underlying encephalopathies and epilepsies improves, there may be greater potential to develop innovative therapies tailored to an individual’s genotype. This article provides an overview of the significant progress in epilepsy genomics in recent years, with a focus on developmental and epileptic encephalopathies in children. The aim of this review is to enhance comprehension of the clinical utilization of genetic testing in this particular patient population. The development of effective and precise therapeutic strategies for epileptic encephalopathies may be facilitated by a comprehensive understanding of their molecular pathogenesis.

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“…To date, 45 different DLG4 variants are reported in the literature. Most of these variants are predicted to result in the premature truncation of the protein product, while seven are missense 1,3 . Nine of the protein‐truncating variants are intronic splice‐site variants localized within five nucleotides from the exon‐intron boundaries and are predicted to affect RNA splicing and lead to a frameshift.…”

Section: Introductionmentioning

confidence: 99%

“…Most of these variants are predicted to result in the premature truncation of the protein product, while seven are missense. 1,3 Nine of the protein-truncating variants are intronic splice-site variants localized within five nucleotides from the exon-intron boundaries and are predicted to affect RNA splicing and lead to a frameshift. As DLG4related synaptopathy is a non-specific syndromic disorder, the diagnosis is mainly genetic, utilizing next generation sequencing based technologies, for example, exome or whole genome sequencing (WGS).…”

mentioning

confidence: 99%

A deep intronic DLG4 variant resulting in DLG4‐related synaptopathy

et al. 2023

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The rare autosomal dominant brain disorder DLG4‐related synaptopathy is caused by de novo variants in DLG4 (encoding PSD‐95), the majority of which are predicted to be protein‐truncating. In addition to splice site variants, a number of synonymous and missense DLG4 variants are predicted to exert their effect through altered RNA splicing, although the pathogenicity of these variants is uncertain without functional RNA studies. Here, we describe a young boy with a deep intronic DLG4 variant (c.2105+235C>T) identified using whole genome sequencing. By using reverse‐transcription PCR on RNA derived from peripheral blood, we demonstrate that DLG4 mRNA expression is detectable in blood and the deep intronic variant gives rise to two alternative DLG4 transcripts, one of which includes a pseudoexon. Both alternative transcripts are out‐of‐frame and predicted to result in protein‐truncation, thereby establishing the genetic diagnosis for the proband. This adds to the evidence concerning the pathogenic potential of deep intronic variants and underlines the importance of functional studies, even in cases where reported tissue‐specific gene expression might suggest otherwise.

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

Cited by 10 publications

References 50 publications

Analysis of trio test in neurodevelopmental disorders

Analysis of trio test in neurodevelopmental disorders

Genetic Testing in Children with Developmental and Epileptic Encephalopathies: A Review of Advances in Epilepsy Genomics

A deep intronic DLG4 variant resulting in DLG4‐related synaptopathy

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