Dataset Information

Characterization of intellectual disability and autism comorbidity through gene panel sequencing.

ABSTRACT: Intellectual disability (ID) and autism spectrum disorder (ASD) are clinically and genetically heterogeneous diseases. Recent whole exome sequencing studies indicated that genes associated with different neurological diseases are shared across disorders and converge on common functional pathways. Using the Ion Torrent platform, we developed a low-cost next-generation sequencing gene panel that has been transferred into clinical practice, replacing single disease-gene analyses for the early diagnosis of individuals with ID/ASD. The gene panel was designed using an innovative in silico approach based on disease networks and mining data from public resources to score disease-gene associations. We analyzed 150 unrelated individuals with ID and/or ASD and a confident diagnosis has been reached in 26 cases (17%). Likely pathogenic mutations have been identified in another 15 patients, reaching a total diagnostic yield of 27%. Our data also support the pathogenic role of genes recently proposed to be involved in ASD. Although many of the identified variants need further investigation to be considered disease-causing, our results indicate the efficiency of the targeted gene panel on the identification of novel and rare variants in patients with ID and ASD.

SUBMITTER: Aspromonte MC

PROVIDER: S-EPMC7428836 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Characterization of intellectual disability and autism comorbidity through gene panel sequencing.

Aspromonte Maria C MC Bellini Mariagrazia M Gasparini Alessandra A Carraro Marco M Bettella Elisa E Polli Roberta R Cesca Federica F Bigoni Stefania S Boni Stefania S Carlet Ombretta O Negrin Susanna S Mammi Isabella I Milani Donatella D Peron Angela A Sartori Stefano S Toldo Irene I Soli Fiorenza F Turolla Licia L Stanzial Franco F Benedicenti Francesco F Marino-Buslje Cristina C Tosatto Silvio C E SCE Murgia Alessandra A Leonardi Emanuela E

Human mutation 20190802 9

Intellectual disability (ID) and autism spectrum disorder (ASD) are clinically and genetically heterogeneous diseases. Recent whole exome sequencing studies indicated that genes associated with different neurological diseases are shared across disorders and converge on common functional pathways. Using the Ion Torrent platform, we developed a low-cost next-generation sequencing gene panel that has been transferred into clinical practice, replacing single disease-gene analyses for the early diagn ...[more]

PMID: 31209962

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Project description:ObjectiveClinical genetic sequencing is frequently utilized to diagnose individuals with neurodevelopmental disorders (NDDs). Here we perform a meta-analysis and systematic review of the success rate (diagnostic yield) of clinical sequencing through next-generation sequencing (NGS) across NDDs. We compare the genetic testing yield across NDD subtypes and sequencing technology.MethodsWe performed a systematic review of the PubMed literature until May 2020. We included clinical sequencing studies that utilized NGS in individuals with epilepsy, autism spectrum disorder (ASD), or intellectual disability (ID). Data were extracted, reviewed, and categorized according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Two investigators performed clinical evaluation and grouping following the International League Against Epilepsy (ILAE) guidelines. Pooled rates of the diagnostic yield and 95% confidence intervals were estimated with a random-effects model.ResultsWe identified 103 studies (epilepsy, N = 72; ASD, N = 14; ID, N = 21) across 32,331 individuals. Targeted gene panel sequencing was used in 73, and exome sequencing in 36 cohorts. Given highly selected patient cohorts, the diagnostic yield was 17.1% for ASD, 24% for epilepsy, and 28.2% for ID (23.7% overall). The highest diagnostic yield for epilepsy subtypes was observed in individuals with ID (27.9%) and early onset seizures (36.8%). The diagnostic yield for exome sequencing was higher than for panel sequencing, even though not statistically significant (27.2% vs 22.6%, P = .071). We observed that clinical sequencing studies are performed predominantly in countries with a high Inequality-adjusted Human Development Index (IHDI) (countries with sequencing studies: IHDI median = 0.84, interquartile range [IQR] = 0.09 vs countries without sequencing studies: IHDI median = 0.56, IQR = 0.3). No studies from Africa, India, or Latin America were identified, indicating potential barriers to genetic testing.SignificanceThis meta-analysis and systematic review provides a comprehensive overview of clinical sequencing studies of NDDs and will help guide policymaking and steer decision-making in patient management.

Dataset Information

Characterization of intellectual disability and autism comorbidity through gene panel sequencing.

Publications

Characterization of intellectual disability and autism comorbidity through gene panel sequencing.

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