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 (NGS) 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 diseasecausing, our results indicate the efficiency of the targeted gene panel on the identification of novel and rare variants in patients with ID and ASD.

Assessment of patient clinical descriptions and pathogenic variants from gene panel sequences in the CAGI‐5 intellectual disability challenge

“…Only one family answered our call, which allowed us to characterize the de novo status of the p.Y381H variant in the CASK gene. Even if the pathogenicity predictions were discordant, this variant was absent from control cohorts and in silico analysis suggested a structural role of this residue in the homo and heterodimerization of the CASK protein (Aspromonte et al, ). The proband phenotype is also consistent with those associated with CASK ‐related disorders.…”

“…This allowed us to observe that variants supporting the predictions of some groups, in particular, Group 1 and Group 3, are rare or common variants with weak pathogenic predictions. Some of these variants were previously excluded by the Padua NDD lab as inherited from healthy parents (Aspromonte et al, ). However, it seems that taking into account the contribution of these inherited rare or common variants may help in the phenotype prediction.…”

Wnt/β-catenin pathway and cell adhesion deregulation in CSDE1-related intellectual disability and autism spectrum disorders

“…Intellectual disability (ID) is a neurodevelopmental condition characterized by significantly impaired intellectual functioning affecting the ability to learn, reasoning and problem solving and by deficits in adaptive behavior, hindering day-to-day social and practical skills (1). ID is usually associated with other co-occurring neurodevelopmental disorders and a large majority of patients with ID also present with features of autism spectrum disorders (ASD).…”

“…ID is usually associated with other co-occurring neurodevelopmental disorders and a large majority of patients with ID also present with features of autism spectrum disorders (ASD). The co-occurrence of these two disease conditions is accounted for by their common molecular and genetic origin as several genes have been shown to be involved in both ID and ASD (1,2). Many of the identified mutations are responsible for dysfunctions of specific key signaling pathways, such as the TGF-β/BMP (Transforming growth factor-beta/bone morphogenetic protein), the Wnt/β-catenin, the SHH (Sonic Hedgehog), and the retinoic acid signaling pathways (reviewed in (3)).…”

Reports from the fifth edition of CAGI: The Critical Assessment of Genome Interpretation

“…CAGI5 continued the emphasis on the interpretation of clinically relevant large‐scale sequence data, with a challenge on the risk of thrombosis in African‐American cohort given whole exome sequence (McInnes et al, ; Wang & Bromberg, ); the identification of variants contributing to intellectual disability phenotypes given gene panel sequence (Aspromonte et al, ; Carraro et al, ; Chen, ); and a challenge of matching whole genome sequences to clinical profiles for patients at Toronto's Hospital for Sick Children (SickKids) and identifying causal variants (Kasak, Hunter et al, ; Pal, Kundu, Yin, & Moult, ). The latter challenge is related to the CAGI4 SickKids challenge, also described in the assessment paper here.…”