CAGI6 ID-Challenge: Assessment of phenotype and variant predictions in 415 children with Neurodevelopmental Disorders (NDDs).

In the context of the Critical Assessment of the Genome Interpretation, 6th edition (CAGI6), the Genetics of Neurodevelopmental Disorders Lab in Padua proposed a new ID-challenge to give the opportunity of developing computational methods for predicting patient's phenotype and the causal variants. Eight research teams and 30 models had access to the phenotype details and real genetic data, based on the sequences of 74 genes (VCF format) in 415 pediatric patients affected by Neurodevelopmental Disorders (NDDs). NDDs are clinically and genetically heterogeneous conditions, with onset in infant age. In this study we evaluate the ability and accuracy of computational methods to predict comorbid phenotypes based on clinical features described in each patient and causal variants. Finally, we asked to develop a method to find new possible genetic causes for patients without a genetic diagnosis. As already done for the CAGI5, seven clinical features (ID, ASD, ataxia, epilepsy, microcephaly, macrocephaly, hypotonia), and variants (causative, putative pathogenic and contributing factors) were provided. Considering the overall clinical manifestation of our cohort, we give out the variant data and phenotypic traits of the 150 patients from CAGI5 ID-Challenge as training and validation for the prediction methods development.

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

The Critical Assessment of Genome Interpretation-5 intellectual disability challenge asked to use computational methods to predict patient clinical phenotypes and the causal variant(s) based on an analysis of their gene panel sequence data. Sequence data for 74 genes associated with intellectual disability (ID) and/or autism spectrum disorders (ASD) from a cohort of 150 patients with a range of neurodevelopmental manifestations (i.e. ID, autism, epilepsy, microcephaly, macrocephaly, hypotonia, ataxia) have been made available for this challenge. For each patient, predictors had to report the causative variants and which of the seven phenotypes were present. Since neurodevelopmental disorders are characterized by strong comorbidity, tested individuals often present more than one pathological condition. Considering the overall clinical manifestation of each patient, the correct phenotype has been predicted by at least one group for 93 individuals (62%). ID and ASD were the best predicted among the seven phenotypic traits. Also, causative or potentially pathogenic variants were predicted correctly by at least one group. However, the prediction of the correct causative variant seems to be insufficient to predict the correct phenotype. In some cases, the correct prediction has been supported by rare or common variants in genes different from the causative one.