The contribution of whole-exome sequencing to intellectual disability diagnosis and knowledge of underlying molecular mechanisms: A systematic review and meta-analysis

Sánchez-Luquez, Karen; Carpena, Marina Xavier; Karam, Simone de Menezes; Tovo‐Rodrigues, Luciana

doi:10.1016/j.mrrev.2022.108428

Cited by 14 publications

(14 citation statements)

References 137 publications

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“…The DRs of the two diagnostic approaches varied in relation to the phenotypic class of referral and, consequently, to the proportion of cases with a defined diagnostic suspect: in our cohort about 31% of patients were enrolled with a diagnostic hypothesis and only 33% of these suspects were confirmed. For the most represented classes in our cohort, malformative pictures and skeletal dysplasias were those with a higher percentage of suspected patients; however, even among these The clinical heterogeneity and ultra-rarity of many genetic conditions together with atypical, nonspecific and composite phenotypes make it difficult to establish an accurate diagnostic suspicion most of the times (Rosina et al, 2022) and particularly for neurodevelopmental disorders, whose differential diagnosis is complicated by a high extent of phenotypic overlap and a constantly increasing number of known causative genes (Sánchez-Luquez et al, 2022). In our cohort, the positive rate of trio-WES in NDDs was considerably higher compared to the traditional approach (36.5% vs. 13%).…”

Section: Discussionmentioning

confidence: 79%

Comparison of first‐tier whole‐exome sequencing with a multi‐step traditional approach for diagnosing paediatric outpatients: An Italian prospective study

Rosina,

Pezzani,

Apuril

et al. 2023

Molec Gen & Gen Med

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BackgroundThe recent guidelines suggest the use of genome‐wide analyses, such as whole exome sequencing (WES), at the beginning of the diagnostic approach for cases with suspected genetic conditions. However, in many realities it still provides for the execution of a multi‐step pathway, thus requiring several genetic tests to end the so‐called ‘diagnostic odyssey’.MethodsWe reported the results of GENE Project (Genomic analysis Evaluation NEtwork): a multicentre prospective cohort study on 125 paediatric outpatients with a suspected genetic disease in which we performed first‐tier trio‐WES, including exome‐based copy number variation analysis, in parallel to a ‘traditional approach’ of two/three sequential genetic tests.ResultsFirst‐tier trio‐WES detected a conclusive diagnosis in 41.6% of patients, way above what was found with routine genetic testing (25%), with a time‐to‐result of about 50 days. Notably, the study showed that 44% of WES‐reached diagnoses would be missed with the traditional approach. The diagnostic rate (DR) of the two approaches varied in relation to the phenotypic class of referral and to the proportion of cases with a defined diagnostic suspect, proving the major difference for neurodevelopmental disorders. Moreover, trio‐WES analysis detected variants in candidate genes of unknown significance (EPHA4, DTNA, SYNCRIP, NCOR1, TFDP1, SPRED3, EDA2R, PHF12, PPP1R12A, WDR91, CDC42BPG, CSNK1D, EIF3H, TMEM63B, RIPPLY3) in 19.4% of undiagnosed cases.ConclusionOur findings represent real‐practice evidence of how first‐tier genome‐wide sequencing tests significantly improve the DR for paediatric outpatients with a suspected underlying genetic aetiology, thereby allowing a time‐saving setting of the correct management, follow‐up and family planning.

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Section: Discussionmentioning

confidence: 79%

Comparison of first‐tier whole‐exome sequencing with a multi‐step traditional approach for diagnosing paediatric outpatients: An Italian prospective study

Rosina,

Pezzani,

Apuril

et al. 2023

Molec Gen & Gen Med

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“…This increase is mainly due to the enhanced ability to diagnose genetic disorders and a consequent surge in the reporting of such disorders within the past decade. With the advent and ease of access to technologies such as Whole Exome Sequencing (WES) and gene panel sequencing, diagnostic rates of genetic disorders have increased significantly (Vaisitti et al, 2021; Sanchez-Luquez et al, 2022; Moundir et al, 2023). In fact, within our set of genetic disorders reported in the UAE, a significant portion comes from the utilization of such high-throughput sequencing techniques on fairly large patient populations (Al-Shamsi et al, 2016; Alsamri et al, 2020; Mahfouz et al, 2020; Saleh et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Spectrum of Genetic Disorders and Gene Variants in the United Arab Emirates National Population: Insights from the CTGA Database

Bizzari

Nair

Hana

et al. 2023

Preprint

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Like many other Arab countries, the United Arab Emirates (UAE) has a relatively high prevalence of genetic disorders. Here we present the first review and analysis of all genetic disorders and gene variants reported in Emirati nationals and hosted on the Catalogue for Transmission Genetics in Arabs (CTGA), an open-access database hosting bibliographic data on human gene variants associated with inherited or heritable phenotypes in Arabs. To date, CTGA hosts 665 distinct genetic conditions that have been described in Emiratis, 621 of which follow a clear Mendelian inheritance. Strikingly, over half of these are extremely rare according to global prevalence rates, predominantly with an autosomal recessive mode of inheritance. This is likely due to the relatively high consanguinity rates within the Emirati population. The 665 conditions include disorders that are unique to the Emirati population, as well as clearly monogenic disorders that have not yet been mapped to a causal genetic locus. We also describe 1,365 gene variants reported in Emiratis, most of which are substitutions and over half are classified as likely pathogenic or pathogenic. Of these, 235 had not been reported on the international databases dbSNP and Clinvar, as of December 2022. Further analysis of this Emirati variant dataset allows a comparison of clinical significance as reported by Clinvar and CTGA, where the latter is derived from the study cited. A total of 306 pathogenic/likely pathogenic variants from CTGA's Emirati dataset, were classified as benign, variants of uncertain significance, or were missing a clinical significance or had not been reported by Clinvar. In conclusion, we present here the spectrum of genetic disorders and gene variants reported in Emiratis. This review emphasizes the importance of ethnic databases such as CTGA in addressing the underrepresentation of Arab variant data in international databases and documenting population-specific discrepancies in variant interpretation, reiterating the value of such repositories for clinicians and researchers, especially when dealing with rare disorders.

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“…The diagnostic yield of ES in GDD/ID individuals with normal genetic screening results ranged from 21 to 66% ( Table 5 ). A recent meta-analysis revealed the average diagnostic yield of ES in individuals with unexplained ID to be 42% [ 62 ]. The diagnostic yield was higher for individuals with trio or familial ES results [ 63 , 64 ].…”

Section: Genetic Diagnostic Tools For Unexplained Intellectual Disabi...mentioning

confidence: 99%

Genome-Wide Sequencing Modalities for Children with Unexplained Global Developmental Delay and Intellectual Disabilities—A Narrative Review

Chen

2023

Children

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Unexplained global developmental delay (GDD) and intellectual disabilities (ID) together affect nearly 2% of the pediatric population. Establishing an etiologic diagnosis is crucial for disease management, prognostic evaluation, and provision of physical and psychological support for both the patient and the family. Advancements in genome sequencing have allowed rapid accumulation of gene–disorder associations and have accelerated the search for an etiologic diagnosis for unexplained GDD/ID. We reviewed recent studies that utilized genome-wide analysis technologies, and we discussed their diagnostic yield, strengths, and limitations. Overall, exome sequencing (ES) and genome sequencing (GS) outperformed chromosomal microarrays and targeted panel sequencing. GS provides coverage for both ES and chromosomal microarray regions, providing the maximal diagnostic potential, and the cost of ES and reanalysis of ES-negative results is currently still lower than that of GS alone. Therefore, singleton or trio ES is the more cost-effective option for the initial investigation of individuals with GDD/ID in clinical practice compared to a staged approach or GS alone. Based on these updated evidence, we proposed an evaluation algorithm with ES as the first-tier evaluation for unexplained GDD/ID.

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The contribution of whole-exome sequencing to intellectual disability diagnosis and knowledge of underlying molecular mechanisms: A systematic review and meta-analysis

Cited by 14 publications

References 137 publications

Comparison of first‐tier whole‐exome sequencing with a multi‐step traditional approach for diagnosing paediatric outpatients: An Italian prospective study

Comparison of first‐tier whole‐exome sequencing with a multi‐step traditional approach for diagnosing paediatric outpatients: An Italian prospective study

Spectrum of Genetic Disorders and Gene Variants in the United Arab Emirates National Population: Insights from the CTGA Database

Genome-Wide Sequencing Modalities for Children with Unexplained Global Developmental Delay and Intellectual Disabilities—A Narrative Review

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